Triazolopyridine jak inhibitor compounds and methods

ABSTRACT

A compound of Formula I, enantiomers, diasteriomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4  and R 5  are defined herein, are useful as JAK kinase inhibitors. A pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of JAK kinase activity in a patient are disclosed.

FIELD OF THE INVENTION

Triazolopyridine compounds of Formula I, which are inhibitors of Januskinases, for example JAK2 kinase, as well as compositions containingthese compounds and methods of use including, but not limited to, invitro, in situ and in Vivo diagnosis or treatment of mammalian cells.

BACKGROUND OF INVENTION

Myeloproliferative disorders (MPD) originate in hematopoietic stem cellsand primarily manifest in elevated counts of mostly normal cells of themyeloid lineage. A primary distinction between Philadelphia-chromosomepositive (Ph+) and Philadelphia-chromosome negative (Ph-−) can be made.Ph+ MPD results in chronic myelogenous leukemia and is driven by abcr-abl fusion protein that drives hematopoietic cell proliferation. Ph−MPD can be further subclassified into three distinct disorders byrelated varieties, namely polycythemia vera (PV), essentialthrombocythemia (ET) and idiopathic myelofibrosis (IMF). Dameshek, W.,Blood 6(4):372-375 (1951). Patients with PV suffer from high counts ofred blood cells, whereas patient with ET have high levels of circulatingplatelets. If left untreated, both diseases can result inlife-threatening thrombotic events. Patients with IMF experiencefibrosis of the bone marrow with subsequent displacement ofhematopoiesis into the spleen and liver. This primarily leads tospenomegaly, which is followed by anemia in later stages of the diseaseas hematopoiesis becomes non-productive. These patients have a poorprognosis, although under certain conditions they can be cured by meansof an allogeneic bone marrow transplant. There is no known cure for Ph−MPD disease.

An activating mutation in the tyrosine kinase JAK2 is associated withPV, ET, IMF and other diseases. Virtually all patients with PV and about50% patients With ET and IMF harbor this mutation. Morgan, K. J. andGilliland, D. G., Ann. Rev. Med. 59:213-222 (2008). The mutation is anexchange from valine to phenylalanine At position 617 in the maturehuman JAK2 protein (V617F). Additional mutations in JAK2 , commonlyfound in exon 12 and referred to as exon 12 mutations, also have anactivating effect and can lead to MPD. Furthermore, a T875N mutation wasassociated with megakaryoblastic leukemia. Finally, JAK2 fusion proteinshave been identified in acute leukemias.

The V617P mutation functions to activate JAK2, which leads to MPD. Innon-mutated form, JAK2 is linked to cytokine receptors (i.e. EPO-R,TPO-R and others) and only gets activated if the receptor itself isactivated by stimulation with the congnate cytokine ligand.Hematopoiesis as a whole is then regulated through the availability ofligands. For example, the cytokine erythropoietin (EPO) stimulateshematopoietic progenitor cells to give rise to red blood cells. Amutation that uncouples JAK2 activation from EPO, therefore, leads toelevated levels of red blood cells. By analogy, thrombopoietin (TPO)regulated platelet growth by binding to the TPO-R, which in turn alsosignals through JAK2. Thus, elevated levels of platelets can also resultfrom aberrant JAK2 activation.

Compounds are needed that inhibit JAK2, which would be beneficial topatients with JAK2 driven myeloproliferative disorders, as well as,other diseases that are responsive to the inhibition of JAK2. Suchdiseases include both diseases in which JAK2 is activated by mutation oramplification, as well as, diseases in which JAK2 activation is a partof the oncogenic cascade. Numerous tumor cell lines and tumor sampleshave high levels of phospho-STAT3, which is a JAK2 target gene.

JAK1 was initially identified in a screen for novel kinases (Wilks, A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607). Genetic andbiochemical studies have shown that JAK1 is functionally and physicallyassociated with the type 1 interferon (e.g., IFNalpha), type IIinterferon (e.g., IFNgamma), IL-2 and IL-6 cytokine receptor complexes(Kissleva et al., 2002, gene 285:1- 24; Levy et al., 2005, Nat. Rev.Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell, 109 (suppl.):S121-S131). JAK1 knockout mice die perinatally due to defects in LIFreceptor signaling (Kisseleva et al., 2002, gene 285:1-24; O'Shea etal., 2002, Cell, 109 (suppl.): S121-S131). Characterization of tissuesderived from JAK1 knockout mice demonstrated critical roles for thiskinase in the IFN, IL-10, IL-2/IL-4, and IL-6 pathways. A humanizedmonoclonal antibody targeting the IL-6 pathway (Tocilizumab) wasrecently approved by the European Commission for the treatment ofmoderate-to-severe rheumatoid arthritis (Scheinecker et al., 2009, Nat.Rev. Drug Discov. 8:273-274).

JAK3 associates exclusively with the gamma common cytokine receptorchain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21cytokine receptor complexes. JAK3 is critical for lymphoid celldevelopment and proliferation and mutations in JAK3 result in severecombined immunodeficiency (SCID) (O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). Based on its role in regulating lymphocytes, JAK3and JAK3-mediated pathways have been targeted for immunosuppressiveindications (e.g., transplantation rejection and rheumatoid arthritis)(Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692: Changelianet al., 2003, Science 302: 875-878).

TYK2 associated with the type I interferon (e.g., IFNalpha), IL-6,IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva et al.,2002, gene 285:1-24; Watford, W. T. & O'Shea, J. J., 2006, Immunity25:695-697). Consistent with this, primary cells derived from a TYK2deficient human are defective in type 1 interferon, IL-6, IL-10, IL-12and IL-23 signaling. A fully human monoclonal antibody targeting theshared p40 subunit of the IL-12 and II-23 cytokines (Ustekinumab) wasrecently approved by the European Commission for the treatment ofmoderate-to-severe plaque psoriasis (Krueger et al., 2007, N. Engl. J.Med. 356:580-92; Reich et al., 2009, Nat. Rev. Drug Discov. 8:355-356).In addition, an antibody targeting the IL-12 and IL-23 pathwaysunderwent clinical trials for treating Crohn'Disease (Mannon et al.,2004, N. Engl. J. Med. 351:2069-79).

SUMMARY OF INVENTION

One embodiment includes a compound of Formula I:

enantiomers, diasteriomers, tautomers or pharmaceutically acceptablesalts thereof, wherein R¹, R², R³, R⁴ and R⁵ are defined herein.

Another embodiment includes a pharmaceutical composition that includes acompound of Formula I and a pharmaceutically acceptable carrier,adjuvant or vehicle.

Another embodiment includes a method of treating or lessening theseverity of a disease or condition responsive to the inhibition of oneor more Janus kinase activity, selected from JAK1, JAK2, JAK3 and TYK2,in a patient. The method includes administering to the patient atherapeutically effective amount of a compound of Formula I.

Another embodiment includes a method of treating or lessening theseverity of a disease or condition responsive to the inhibition of JAK2kinase activity in a patient. The method includes administering to thepatient a therapeutically effective amount of a compound of Formula I.

Another embodiment includes a kit for treating a disease or disorderresponsive to the inhibition of a JAK kinase. The kit includes a firstpharmaceutical composition comprising a compound of Formula I andinstructions for use.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments, examples ofwhich are illustrated in the accompanying structures and formulas. Whilethe invention will be described in conjunction with the enumeratedembodiments, it will be understood that they are not intended to limitthe invention to those embodiments. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims. One skilled in the art will recognize manymethods and materials similar or equivalent to those described herein,which could be used in the practice of the present invention. Thepresent invention is in no way limited to the methods and materialsdescribed. In the event that one or more of the incorporated literature,patents, and similar materials differs from or contradicts thisapplication, including but not limited to defined terms, term usage,described techniques, or the like, this application controls.

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical, wherein the alkyl radical may beoptionally substituted independently with one of more substituentsdescribed herein. In one example, the alkyl radical is one to eighteencarbon atoms (C₁-C₁₈). In other examples, the alkyl radical is C₀-C₆,C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, or C₁-C₃.Examples of alkyl groups include C₁-C₈ hydrocarbon moieties such asmethyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl i-Bu, i-butyl, —CH₂CH(CH₃)₂),2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu,t-butyl, —C(CH

)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—CH₂CH₂CH(CH₃)₂),2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃),2-hexyl (—CH(CH₃)CH₃CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)(CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃₎ ₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl and 1-octyl.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical with at least one site of unsaturation, i.e., acarbon-carbon double bond, wherein the alkenyl radical may be optionallysubstituted independently with one or more substituents describedherein, and includes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. In one example, the alkenylradical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, thealkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃. Examplesinclude, but are not limited to, ethenyl or vinyl (—CH═CH₂), prop-1-enyl(—CH═CHCH₃), prop-2-enyl (—CH₂CH═CH₂), 2-methylprop-1-enyl, but-1-enyl,but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene,hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hexa-1,3-dienyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical with at least one site of unsaturation, i.e., a carbon-carbon,triple bond, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein. In oneexample, the alkynyl radical is two to eighteen carbon atoms (C₂-C₁₈).In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆or C₂-C₃. Examples include, but are not limited to, ethynyl (—C═CH),prop-1-ynyl (—C═CCH₃), prop-2-ynyl (propargyl —CH₂C═CH), but-1-ynyl,but-2-ynyl and but-3-ynyl.

“Cycloalkyl” refers to a non-aromatic, saturated or partiallyunsaturated hydrocarbon ring group wherein the cycloalkyl group may beoptionally substituted independently with one or more substitutentsdescribed herein. In one example, the cycloalkyl group is 3 to 12 carbonatoms (C₃-C₁₂). In other examples, cycloalkyl is C₃-C₁₀ or C₅-C₁₀. Inother examples, the cycloalkyl group, as a monocycle, is C₃-C₆ Or C₅-C₆.In another example, the cycloalkyl group, as a bicycle, is C₇-C₁₂.Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements ofbicyclic cycloalkyls having 7 to 12 ring atoms include, but are notlimited to [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplarybridged bicyclic cycloalkyls include, but are not limited to,bicyclo[2.2.2]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.

“Aryl” refers to a cyclic aromatic hydrocarbon group optionallysubstituted independently with one or more substituents describedherein. In one example, the aryl group is 6-20 carbon atoms (C₆-C₂₀). Inanother example, the aryl group is C₆-C₉. In another example, the arylgroup is a C₆ aryl group. Aryl groups may be represented in theexemplary structures as “Ar”. Aryl includes a bicyclic group comprisingan aromatic ring with a fused non-aromatic or partially saturated ring.Example aryl groups include, but are not limited to, phenyl,naphthalenyl, anthracenyl, indenyl, indanyl, 1,2-dihydronapthalenyl,1,2,3,4-tetrahydronapthyl, and the like.

“Halo” refers to F, Cl, Br or I.

“Heterocyclyl” refers to a saturated or a partially unsaturated (i.e.,having one or more double and/or triple bonds within the ring) cyclicgroup in which at least one ring atom is a heteroatom independentlyselected from nitrogen, oxygen, phosphorus and sulfur, the remainingring atoms being carbon. The heterocyclyl group may be optionallysubstituted with one or more substituents described below. In onembodiment, heterocyclyl includes monocycles or bicycles having 1 to 9carbon ring members (C₁-C₉). In other examples, heterocyclyl includesmonocycles or bicycles having C₁-C₅, C₃-C₅ or C₄-C₅. Examples of bicyclesystems include, but are not limited, to, [3,5], [4,5], [5,5], [3,6],[4,6], [5,6], or [6,6] systems. In another embodiment, heterocyclylincludes bridged ring systems having [2.2.1], [2.2.2], [3.2.2] and[4.1.0] arrangements, and having 1 to 3 heteroatoms selected from N, O,S and P. In another embodiment, heterocyclyl includes spiro groupshaving 1 to 3 heteroatoms selected from N, O, S and P. The heterocyclylgroup may be a carbon-linked group or heteroatom-linked group.“Heterocyclyl” includes a heterocyclyl group fused to a cycloalkylgroup.

Exemplary heterocyclyl groups include, but are not limited to, oxiranyl,aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl,1,3-dithietanyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl,homopiperdinyl, oxepanyl, thiepanyl, oxaepinyl, diazepinyl, thiazepinyl,dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl,tetrahydrothienyl, tetrahydorpyranyl, tetrahydrothiopyranyl,1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl,dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, imidazolidinyl,3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl andazabicyclo[2.2.2]hexanyl. Examples of a heterocyclyl group wherein aring atom is substituted with oxo (═O) are indolinonyl, pyrimidinonyland 1,1-dioxo-thiomorpholinyl. The heterocyclyl groups herein areoptionally substituted independently with one or more substituentsdescribed herein. Heterocyles are described in Paquette, Leo A.;“Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York,1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566.

The term “heteroaryl” refers to an aromatic carbocyclic radical in whichat least one ring atom is a heteroatom independently selected fromnitrogen, oxygen and sulfur, the remaining ring atoms being carbon.Heteroaryl groups may be optionally substituted with one or moresubstituents described herein. In one example, the heteroaryl groupcontains 1 to 9 carbon ring atoms (C₁-C₉). In other examples, theheteroaryl group is C₁-C₅, C₃-C₅ or C₅-C₁₀. In one embodiment, exemplaryheteroaryl groups include monocyclic aromatic 5-, 6- and 7-memberedrings containing one or more heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In another embodiment, exemplaryheteroaryl groups include fused ring systems of 8 to 20 atoms wherein atlease one aromatic ring contains one or more heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. “Heteroaryl” includesheteroaryl groups fused with an aryl, cycloalkyl or heterocyclyl group.Examples of heteroaryl groups include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

In certain embodiments, the heterocyclyl or heteroaryl group isC-attached. By way of example and not limitation, carbon bondedheterocyclyls include bonding arrangements at position 2, 3, 4, 5, or 6of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5,or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2,3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole ortetrahydorpyrrole, position 2, 4, or 5 of a oxazole, imidazole orthiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine,position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5,6, 7, or 8 of an isoquinoline (2-pyridyl, 3-pyridyl, 4-pyridyl,5-pyridyl, 6-pyridyl).

In certain embodiments, the heterocyclyl or heteroaryl group isN-attached. By way of example and not limitation, the nitrogen bondedheterocyclyl or heteroaryl group include bonding arrangements atposition 1 of a aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline,3-pyrroline, imidazole, imidazolidine, 2-imidazole, 3-imidazoline,pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine,piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, orisoindoline, position 4 of a morpholine, and position 9 of a carbazole,or β-carboline.

In an embodiment, for Formula I, alkyl, alkenyl and alkynyl areoptionally substituted by 1 to 5 substituents independently selectedfrom by one or more OR^(a), NR^(c)R^(d), oxo and halo, and aryl,heterocyclyl, heteroaryl and cycloalkyl are optionally substituted by 1to 5 substituents independently selected from OR^(a), oxo, halo, CF₃,NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl), wherein R^(a), R^(c) andR^(d) are defined below for Formula I. In another embodiment, forFormula I, alkyl, alkenyl and alkynyl are optionally substituted by 1 to3 substituents independently selected from by one or more OR^(a),NR^(c)R^(d), oxo and halo, and aryl, heterocyclyl, heteroaryl andcycloalkyl are optionally substituted by 1 to 3 substituentsindependently selected from OR^(a), oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄alkyl and C(O)(C₁-C₄ alkyl), wherein R^(a), R^(c) and R^(d) are definedbellow for Formula I.

In an embodiment, for Formula I, alkyl, alkenyl and alkynyl areoptionally substituted by 1 to 5 substituents independently selectedfrom oxo and halo, and aryl is optionally substituted by 1 to 5substituents independently selected from OR^(a), halo, CF₃, NR^(c)R^(d),C₁-C₄ alkyl, wherein R^(a), R^(c) and R^(d) are defined bellow forFormula I. in another embodiment, for Formula I, alkyl, alkenyl andalkynyl are optionally substituted by 1 to 3 substituents independentlyselected from oxo and halo, and aryl is optionally substituted by 1 to 3substituents independently selected from OR^(a), halo, CF₃, NR^(c)R^(d),and C₁-C₄ alkyl, wherein R^(a), R^(c) and R^(d) are defined below forFormula I.

In an embodiment, for Formula I, alkyl, aryl and cycloalkyl areoptionally substituted by 1 to 5 substituents independently selectedfrom C₁-C₄ alkyl, (C₀-C₃ alkyl)OR_(c), oxo, halo, NR^(c)R^(d), C₄-C₅heterocyclyl, wherein R^(c) and R^(d) are defined below for Formula I.In another embodiment, for Formula I, alkyl, aryl and cyclalkyl areoptionally substituted by 1 to 3 substituents independently selectedfrom C₁-C₄ alkyl, (C₀-C₃ alkyl)OR

, oxo, halo, NR^(c)R^(d), C₄-C₅ heterocyclyl, wherein R^(c) and R^(d)are defined below for Formula I.

In an embodiment, for Formula I, alkyl, cycloalkyl and phenyl areoptionally substituted by 1 to 5 substituents independently selectedfrom halo, CH₃ OH, NH₂, C(O)O(C₁-C₆ alkyl) and C(O)NH(C₁-C₆ alkyl). Inanother embodiment, for Formula I, alkyl, cycloalkyl and phenyl areoptionally substituted by 1 to 3 substituents independently selectedfrom halo, CH₃ OH, NH₂, C(O)O(C₁-C₆ alkyl) and C(O)NH(C₁-C₆ alkyl).

“Treat” and “treatment” includes both therapeutic treatment andprophylactic or preventative measure, wherein the object is to preventor slow down (lessen) an undesired physiological change or disorder,such as the development or spread of cancer. For purposes of thisinvention, beneficial or desired clinical results include, but are notlimited to, alleviation of symptoms, diminishment of extent of disease,stabilized (i.e., not worsening) state of disease, delay or slowing ofdisease progression, amelioration or palliation of the disease state,and remission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment. Those in need oftreatment include those already with the condition or disorder as wellas those prone to have the condition or disorder, (for example, througha genetic mutation) or those in which the condition or disorder is to beprevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells,reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can, for example, bemeasure by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

The term “bioavailablility” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

The term “cancer” and “cancerous” refer to or describe the physiologicalcondition in mammals that is typically characterized by unregulated cellgrowth. A “tumor” comprises one or more cancerous cells. Examples ofcancer include, but are not limited to, carcinoma, lymphoma, blastoma,sarcoma, and leukemia or lymphoid malignancies. More particular examplesof such cancers include squamous cell cancer (e.g., epithelial squamouscell cancer), lung cancer including small-cell lung cancer, non-smallcell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamouscarcinoma of the lung, cancer of the peritoneum, hepatocellular cancer,gastric or stomach cancer including gastrointestinal cancer, pancreaticcancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer,colorectal cancer, endometrial or uterine carcinoma, salivary glandcarcinoma, kidney or renal cancer, prostate cancer, vulval cancer,thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, aswell as head and neck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of chemotherapeutic agents in Erlotinib(TARCEVA®, Genetech, Inc./OSI Pharm.), Trastuzumab (HERCEPTIN®,Genetech, Inc.); bevacizumab (AVASTIN®, Genetech, Inc.); Rituximab(RITUXAN®, Genentech, Inc./Biogen Idee, Inc.), Bortezomib (VELCADE®,Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent(SUI1248, Pfizer), Letrozole (FEMARA®, Novarits), Imatinib mesylate(GLEEVEC®, Novartis), PTK787/ZK 222584 (Novaritis), Oxaliplatin(Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin(Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (GSK572016, Glaxo Smith Kline),Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), andGefitinib (IRESSA®, AstraZeneca), AG1478, AGI571 (SU 5271; Sugen),alkylating agents such as thiotepa and CYTOXAN®cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopam and uredopa; ethylenimines andmethylamelamines including altretamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylomelamine actogenins (especially bullatacin and bullatacinone);a campgtothecin (including the synthetic analog topotecan); bryostatin;callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesinsynthetic analogs; cryptophycins (particularly cryptophycin 1 andcryptophycin 8); dolastatin; duocarmycin (including the syntheticanalogs, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; asarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,chlornaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosureas such as carmustine, chlorozoticin, fotemustine, lomustine,nimustine, and ranimustine; antibiotics such as the enediyne antibiotics(e.g., calicheamicin, especially calicheamicin gammal

and calicheamicin omegal

(Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); dynemicin, includingdynemicin A; bisphosphonates, such as clodronate; an esperamicin; aswell as neocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, a

thramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin),morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolin-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-flourouracil (5-FU); folic acid analogs such as denopterin,methodtrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,meptitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane, folic acid replenisher such as frolinic acid;aceglatone, aldophsphamide glycoside; aminolevulinic acid; eniluracilamsacrine; bestrabucil; bisantrene; edatraxate; defofamine, demecolcine;diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene Oreg.); razoxane; rhizoxin;sizofiran; spirogermanium; temuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL®(pacluitaxel; Bristol-Myers Squibb Oncolog, Princeton, N.J.), ABRAXANE®(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (doxetaxil; Rhōne-Poulenc Rorer, Antony, France);chloranbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin;vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate;daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomeraseinhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such asretinoic acid; capecitabine; and pharmaceutically acceptable salts,acids and derivatives of any of the above.

Also included in the definition of “chempotherapeutic agent” are (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifen, LYI- 17018, onapristone, and FARESTON® (tormifinecitrate); (ii) araomatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as fiutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribosomes such as VEGFinhibitors (e.g., ANGIOZYME®) and (viii) vaccines such as gene therapyvaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®, PROLEUKIN®rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®, ABARELIX® rmRH;(ix) anti-angiogenic agents; and (x) pharmaceutically acceptable salts,acids and derivatives of any of the above.

Humanized monoclonal antibodies with therapeutic potential as agents incombination with the Janus kinase inhibitors of the invention include:alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab,bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab,certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab,efaizumab, epratuxzumab, erlizumab, flevizumab, fontolizumab, gemtuzumabozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab,matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab,nimotuzumab, nolovisumab, numavizumab, ocrelizumab, omalizumab,palivizumab, pascolizumab, pecfusituzumab, pectuzuma, pertuzuma,pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab,resyvixumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab,sontuzumab, tacatuzumab tetraxetan, tadocizumba, talizumab, tefibazumab,tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin,tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab,adalimumab, etancercept, infliximab and the anti-interleukin-12(ABT-874/J695, Wyeth Research and Abbott Laboratories) which is arecombinant exclusively human-sequence, full-length IgG

λ antibody genetically modified to recognize interleukin-12 p40 protein.

The term “prodrug” as used in this application refers to a precursor ofderivative form of a pharmaceutically active substance that is lessefficacious to the patient or cytotoxic to tumor cells compared to theparent drug and is capable of being enzymatically or hydrolyticallyactivated or converted into the more active parent form. See, e.g.,Wilman, “Prodrugs in Cancer Chemotherapy” Biochemical SocietyTransactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stellaet al., “Prodrugs: A Chemical Approach to Targeted Drug Delivery,”Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, HumanaPress (1985). The prodrugs of this invention include, but are notlimited to, phosphate-containing prodrugs, thiophosphate-containingprodrugs, sulfate-containing prodrugs, peptide-containing prodrugs,D-amino acid-modified prodrugs, glycosylated prodrugs,β-lactam-containing prodrugs, optionally substitutedphenoxyacetamide-containing prodrugs or optionally substitutedphenylacetamide-containing prodrugs, 5-fluorocytosine and other5-fluoridine prodrugs which can be converted into the more activecytotoxic free drug. Example of cytotoxic drugs that can be derivatizedinto a prodrug form for use in this invention include, but are notlimited to, those chemotherapeutic agents described above.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactant which is useful for delivery of a drug(such as a compound of Formula I and, optionally, a chemotherapeuticagent) to a mammal. The components of the liposome are commonly arrangedin a bilayer formation, similar to the lipid arrangement of biologicalmembranes.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indication, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. Many organic compounds exist in optically active forms,i.e., they have the ability to rotate the plane of plane-polarizedlight. In describing an optically active compound, the prefixes D and L,or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The prefixes d and l or (+) and (−)are employed to designate the sign of rotation of plane-polarized lightby the compound, with (−) or l meaning that the compound islevorotatory. A compound prefixed with (+) or d is dextrorotatory. For agiven chemical structure, these stereoisomers are identical except thatthey are mirror images of one another. A specific stereoisomer may alsobe referred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric mixture. A 50:50 mixture of enantiomers isreferred to as a racemic mixture or a racemate, which may occur wherethere has been no stereoselection or stereospecificity in a chemicalreaction or process. The terms “racemic mixture” and “racemate” refer toan equimolar mixture of two enantiomeric species, devoid of opticalactivity.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofFormula I. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccarate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate, (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.A pharmaceutically acceptable salt may involve the inclusion of anothermolecule such as an acetate ion, a succinate ion or other counter ion.The counter ion may be any organic or inorganic moiety that stabilizesthe charge on the parent compound. Furthermore, a pharmaceuticallyacceptable salt may have more than one charged atom in its structure.Instances where multiple charged atoms are part of the pharmaceuticallyacceptable salt can have multiple counter ions. Hence, apharmaceutically acceptable salt can have one or more charged atomsand/or one or more counter ion.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of Formula I. Examples of solvents that formsolvates include, but are not limited to, water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term“hydrate” refers to the complex where the solvent molecule is water.

The term “protecting group” or “Pg” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,phthalimido, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable hydroxy-protecting groupsinclude acetyl, trialkylsilyl, dialkylphenylsilyl, benzolyl, benzyl,benzyloxymethyl, methyl, methoxymethyl, triarylmethyl, andtetrahydropyranyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene and P.Wuts, Protective Groups in Organic Synthesis, Third Ed., John Wiley &Sons, New York, 1999, and P. Kocienski, Protecting Groups, Third Ed.,Verlag, 2003.

The term “patient” includes human patients and animal patients. The term“animal” includes companion animals (e.g., dogs, cats and horses),food-source animals, zoo animals, marine animals, birds an other similaranimal species.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The terms “compound of this invention,” and “compounds of the presentinvention”, and “compounds of Formula I”, unless otherwise indicated,include compounds of Formula I and stereoisomers, tautomers, solvates,metabolites, salts (e.g., pharmaceutically acceptable salts) andprodrugs thereof. Unless otherwise stated, structures depicted hereinare also meant to include compounds that differ only in the presence ofone or more isotopically enriched atoms. For example, compounds ofFormula I, wherein one or more hydrogen atoms are replaced deuterium ortritium, or one or more carbon atoms are replaced by a ¹³C- or¹⁴C-enriched carbon are within the scope of this invention.

“Inflammatory disorder” as used herein can refer to any disease,disorder, or syndrome in which an excessive or unregulated inflammatoryresponse leads to excessive inflammatory symptoms, host tissue damage,or loss of tissue function. “Inflammatory disorder” also refers to apathological state mediated by influx of leukocytes and/or neutrophilchemotaxis.

“Inflammation” as used herein refers to a localized, protective responseelicited by injury or destruction of tissues, which serves to destroy,dilute, or wall of (sequester) both the injurious agent and the injuredtissue. Inflammation is notably associated with influx of leukocytesand/or neutrophil chemotaxis. Inflammation can result from infectionwith pathogenic organisms and viruses and from noninfectious means suchas trauma or reperfusion following myocardial infarction or stroke,immune response to foreign antigen, and autoimmune responses.Accordingly, inflammatory disorders amenable to treatment with Formula Icompounds encompass disorders associated with reactions of the specificdefense system as well as with reactions of the nonspecific defensesystem.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune disease,and delayed type hypersensitivity response mediated by T-cells. Chronicinflammatory disease, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

The term “nonspecific defense system” as used herein refers toinflammatory disorders that are mediated by leukocytes that areincapable of immunological memory (e.g., granulocytes, and macrophages).Examples of inflammation that result, at least in part, from a reactionof the nonspecific defense system include inflammation associated withconditions such as adult (acute) respiratory distress syndrome (ARDS) ormultiple organ injury syndromes; reperfusion injury; acuteglomerulonephritis; reactive arthritis; dermatoses with acuteinflammatory components, acute purulent meningitis or other centralnervous system inflammatory disorders such as stroke; thermal injury;inflammatory bowel disease; granylocyte transfusion associatedsyndromes; and cytokine-induce toxicity.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediatory (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclearleukocytes such as neutrophils, basophils, and eosinophils), mast cells,dendritic cells, Langerhans cells, and endothelial cells.). It will beappreciated by persons skilled in the art that the activation of one ora combination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory disorder.

The term “NSAID” is an acronym for “non-steroidal anti-inflammatorydrug” and is a therapeutic agent with analgesic, antipyretic (loweringan elevated body temperature and relieving pain without impairingconsciousness) and, in higher doses, with anti-inflammatory effect(reducing inflammation). The term “non-steroidal” is used to distinguishthese drugs from steroids, which (among a broad range of other effects)have a similar eicosanoid-depressing, anti-inflammatory action. Asanalgesics, NSAIDs are unusual in that they are non-narcotic. NSAIDsinclude aspirin, ibuprofen, and naproxen. NSAIDs are usually indicatedfor the treatment of acute or chronic conditions where pain andinflammation are present. NSAIDs are generally indicated for thesymptomatic relief of the following conditions: rheumatoid arthritis,osteoarthritis, inflammatory arthropathies (e.g. ankylosing spondylitis,psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea,metastatic bone pain, headache and migraine, postoperative pain,mild-to-moderate pain due to inflammation and tissue injury, pyrexia,ileus, renal colic. Most NSAIDs act as non-selective inhibitors of theenzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) andcyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyzes theformation of prostaglandins and thromboxane from arachidonic acid(itself derived from the cellular phospholipid bilayer by phospholipaseA₂). Prostaglandins act (among other things) as messenger molecules inthe process of inflammation. COX-2 inhibitors include celecoxib,etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, andvaldecoxib.

“JAK kinase,” and “Janus kinase” refer to the JAK1, JAK2, JAK3 and TYK2protein kinases.

Triazolopyridine JAK Inhibitor Compounds

In one embodiment, a compound of Formula I, and pharmaceuticalformulations thereof, are provided that are useful in the treatment ofdiseases, conditions and/or disorders responsive to the inhibition ofJAK kinases.

Another embodiment includes compound of Formula I

enantiomers, diasteriomers, tautomers or pharmaceutically acceptablesalts thereof, wherein:

R¹ is H, C(O)OR

, phenyl, C₁-C

heterocyclyl or C₁-C₉ heteroaryl, wherein said phenyl, and heteroarylare optionally substituted by 1 to 5 R⁶;

R² is a phenyl, C₁-C₉ heteroaryl or C₁-C₉ heterocyclyl, wherein thephenyl, heteroaryl and heterocyclyl are optionally substituted by 1 to 5R⁷;

R³, R⁴ and R⁵ are independently H, CH₃, CH₂CH₃, OCH₃CF, F or Cl;

R⁶ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆alkyl)OR^(a), (C₀-C₆ alkyl)NR^(a)R^(b), halo, CN, CF₃,S(O)O₁₋₂NR^(a)R^(b), C(O)R

, NR^(a)C(O)OR^(b), NR

S(O)₁₋₂NR^(b), (C₀-C₆ alkyl)C₁-C₅ heteroaryl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl, (C₀-C₆ alkyl)C₃-C₆ cycloalkyl, (C₀-C₆ alkyl)C₆-C₉ aryl,(C₀-C₆ alkyl)C(O)OR

, C(O)O(C₀-C₅ alkyl)NR_(a)R^(b), C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl), C(O)NR^(a)(C₀-C₅alkyl)(C₃-C₆ cycloalkyl), C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heteroaryl),C(O)NR^(a)(C₁-C₅ alkyl)NR^(a)R^(b) or C(O)NR^(a)(C₀-C₅ alkyl)(C₆ aryl),wherein said alkyl, alkenyl and alkynyl are optionally substituted by 1to 5 substituents independently selected from OR^(a), NR^(c)R_(d), oxoand halo, and said aryl, heterocyclyl, heteroaryl and cycloalkyl areoptionally substituted by 1 to 5 substituents independently selectedfrom OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl and C(O)(C₁-C₄ ;

R⁷ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), (C₀-C₆ alkyl) (C₆-C₉ aryl), halo,C(O)NR^(a)R^(b), NR^(a)C(O)R^(b), SO₂(C₁-C₆ alkyl), SO₂NR^(a)R^(b), CN,CF₃, CH₂CF³, nitro, S(O)(C₁-C₆ alkyl), S(O)NR^(a)R^(b), NR³S(O)₁₋₂R^(b),C(O)R

, C(O)OR

, (C₀-C₆ alkyl)C₁-C₅ heteroaryl, (C₀-C₆ alkyl)C₁-C₅ heterocyclyl or(C₀-C₆ alkyl)C₃-C₆ cycloalkyl, wherein said alkyl, alkenyl and alkynylare optionally substituted by 1 to 5 substituents independently selectedfrom oxo, NR^(a)R^(b), OR

, and halo, and said aryl, heteroaryl, heterocyclyl and cycloalkyl areoptionally substituted by 1 to 5 substituents independently selectedfrom OR

, halo, CF₃, NR^(c)R^(d) and C₁-C₄ alkyl;

R^(a) R^(b) are independently H, OR

, C(O)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C₆ aryl or C₃ -C₆ cycloalkyl, whereinsaid alkyl, aryl and cycloalkyl are optionally substituted by 1 to 5substituents independently selected from C₁-C₄ alkyl, (C₀-C₃alkyl)OR^(c), oxo, halo, NR^(c)R^(d) and C₄-C₅ heterocyclyl; or

R^(a) and R^(b) together with the atom to which they are attached form aC₁-C₅ heterocyclyl; and

R^(c) and R^(d) are independently H, C₁-C₃ alkyl, C₃-C₆ cycloalkyl orphenyl, wherein said alkyl, cycloalkyl and phenyl are optionallysubstituted by 1 to 5 substituents independently selected from halo,CH₃, OH or NH₂, C(O)O(C₃-C

alkyl) and C(O)NH(C₁-C₆ alkyl).

Another embodiment includes compounds of Formula I:

enantiomers, diasteriomers, tautomers or pharmaceutically acceptablesalts thereof, wherein:

R¹ is H, C(O)OR

, phenyl or C₁-C₉ heteroaryl, wherein said phenyl and heteroaryl areoptionally substituted by 1 to 6 R⁶

R² is phenyl, C₁-C₉ heteroaryl or C₁-C₉ heterocyclyl, wherein thephenyl, heteroaryl and heterocyclyl are optionally substituted by 1 to 6R⁷;

R³, R⁴ and R⁵ are independently H, CH₃, CH₂CH₃, CF₃, F or Cl;

R⁶ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆alkyl)OR^(a), (C₀-C₆ alkyl)NR^(a)R^(b), halo, CN, C₁-C₅ heteroaryl,C₁-C₅ heterocyclyl, C₃-C₆ cyclalkyl, C₆-C₉ aryl, C(O)OR

, C(O)(C₀-C₅ alkyl)NR^(a)R^(b), C(O)(C₀-C₅ alkyl)(C₁-C₅ Heterocyclyl),C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl), C(O)NR^(a)(C₀-C₅alkyl)(C₃-C₆ cycloalkyl), C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heteroaryl, C(O)NR^(a)(C₁-C₅ alkyl)NR^(a)R^(b),C(O)NR

(C₁-C₅ alkyl)(C₆ aryl), wherein said alkyl, alkenyl and alkynyl areoptionally substituted by 1 to 5 substituents independently selectedfrom OR

, NR^(c)R^(d), oxo, and halo, and said aryl, heterocyclyl, heteroaryland cycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR^(a), oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄alkyl and C(O)(C₁-C₄ alkyl);

R⁷ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆alkyl)OR^(a), (C₀-C₆ alkyl)NR^(a)R^(b), (C₀-C₆ alkyl)(C₆-C

aryl), halo, C(O)NR^(a)R^(b), NR^(a)C(O)R^(b), SO₂(C₁-C₆ alkyl),SO₂NR^(a)R^(b), CN, nitro, wherein said alkyl, alkenyl and alkynyl areoptionally substituted by 1 to 5 substituents independently selectedfrom oxo and halo, and said and said aryl is optionally substituted by 1to 5 substituents independently selected from OR³, halo, CF₃,NR^(c)R^(d) and C₁-C₄ alkyl;

R^(a) and R^(b) are independently H, OR^(c)C(O)O(C₁-C_(6 alkyl) C) ₁-C₆alkyl, C₆ aryl or C₃-C₆ cycloalkyl, wherein said alkyl, aryl andcycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from C₁-C₄ alkyl, (C₀-C₃ alkyl)OR

, oxo, halo, NR^(c)R^(d) and C₄-C₅ heterocyclyl; or

R^(a) and R^(b) together with the atom to which they are attached form aC₁-C₅ heterocyclyl; and

R^(c) R^(d) are independently H, C₁-C₃ alkyl, C₃-C₆ cycloalkyl orphenyl, wherein said alkyl, cycloalkyl and phenyl are optionallysubstituted by 1 to 5 substituents independently selected from halo,CH₃, OH, NH₂, C(O)O(₁-C₆ alkyl) and C(O)NH(C₁-C₆ alkyl).

In one embodiment, R¹ is phenyl or C₁-C₉ heteroaryl, wherein said phenyland heteroaryl are optionally substituted by 1 to 5 R⁶.

In one embodiment, R¹ is phenyl optionally substituted by 1 to 5 R⁶.

In one embodiment, R¹ is phenyl optionally substituted by 1 to 3 R⁶.

In one embodiment, R¹ is phenyl optionally substituted by 2 R⁶.

In one embodiment, R¹ is phenyl optionally substituted by 1 R⁶.

In one embodiment, R¹ is phenyl optionally substituted by 1 to 5 R⁶.

In one embodiment, C₁-C₉ heteroaryl is pyridinyl, imidazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, trazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinoxalinyl, quinoxalinyl, naphthyridinyl or furopyridinyl, each ofwhich is optionally substituted by 1 to 5 R⁶.

In one embodiment, R¹ is pyridinyl optionally substituted by 1 to 4 R⁶.

In one embodiment, R¹ is pyridinyl optionally substituted by 2 R⁶.

In one embodiment, R¹ is pyridinyl optionally substituted by 1 R⁶.

In one embodiment, R¹ is H.

In one embodiment, R¹ is C(O)OR^(a), wherein R

is independently H, OR^(c), C(O)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C₆ aryl orC₃-C₆ cycloalkyl, wherein said alkyl, aryl, and cycloalkyl areoptionally substituted by 1 to 5 substituents independently selectedfrom C₁-C₄ alkyl, (C₀-C₃ alkyl)OR

, oxo, halo, NR^(c)R^(d) and C₄-C₅ heterocyclyl.

In one embodiment, R¹ is phenyl or C₁-C₉ heteroaryl, optionallysubstituted by 1 to 3 R⁶. In one example, R¹ is phenyl, pyrazolyl,benzimidazolyl or pyridyl, optionally substituted by 1 to 3 R⁶. In oneexample, R¹ is phenyl, pyrazolyl or pyridyl, optionally substituted by 1to 3 R⁶, wherein R⁶ is independently C₁-C₆ alkyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), halo, CF₃, C(O)OR^(a), C(O)(C₀-C₅alkyl)NR^(a)R^(b), C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),C(O)NR^(a)(C₀-C₅ alkyl(C₁-C₅ heterocyclyl), C(O)NR^(a)(C₀-C₅alkyl)(C₃-C₆ cycloalkyl), C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heteroaryl),C(O)NR^(a)(C₀-C⁵ alkyl)NR^(a)R^(b), C(O)NR^(a)(C₁-C₅ alkyl)(C₆ aryl),wherein said alkyl is optionally substituted by 1 to 5 substituentsindependently selected from OR

, NR^(c)R^(d), oxo, halo, and said aryl, heterocyclyl, heteroaryl andcycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl and C(O)(C₁-C₄ alkyl). In one example, R¹ is phenyl,pyrazolyl or pyridyl, optionally substituted by 1 R⁶, wherein R⁶ isindependently C(O)OR^(a), C(O)(C₀-C₅ alkyl)NR^(a)R^(b), C(O)(C₀-C₅alkyl)(C₁-C₅ heterocyclyl), C(O)NR

(C₀-C₅ alkyl)(C₁-C

heterocyclyl), C(O)NR^(a)(C₀-C⁵ alkyl)(C₃-C₆ cycloalkyl),C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heteroaryl), c(O)NR

^((C) ₁-C₅ alkyl)R^(a)R^(b), C(O)NR

(C₀-C₅ alkyl)(C₆ aryl), wherein said alkyl is optionally substituted by1 to 5 substituents independently selected from OR^(a), NR^(c)R^(d), oxoand halo, and said aryl, heterocyclyl, heteroaryl and cycloalkyl areoptionally substituted by 1 to 5 substituents independently selectedfrom OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl and C(O)(C₁-C₄ alkyl).

In one embodiment, R¹ is phenyl or pyridinyl, optionally substituted by1 to 3 R⁶, wherein R⁶ is independently C₁-C₃ alkyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR_(a)R^(b), halo, CF₃, S(O)₁₋₂NR^(a)R^(b), NR

S(O)₁₋₂NR^(a)R^(b), (C₀-C₅ alkyl)C₁-C₅ heterocyclyl or C(O)OR

, wherein said alkyl is optionally substituted by 1 to 5 substituentsindependently selected from OR

, NR^(c)R^(d), oxo, S(O)₁₋₂R

, S(O)₁₋₂NR^(a)R^(b) and halo, and said heterocyclyl is optionallysubstituted by 1 to 3 substituents independently selected from (C₀-C₅alkyl)OR^(a), oxo, halo, CF₃, (C₀-C₅ alkyl)NR^(c)R^(d), C₁-C⁴ alkyl andC(O)R

. In one example, R¹ is selected from the following:

wherein the wavy line represents the point of attachment to Formula I.

In one embodiment, R¹ is phenyl or pyridinyl, optionally substituted by1 R⁶, wherein R⁶ is independently C(O)(C₀-C₅ alkyl)NR^(a)R^(b),C(O)NR^(a)(C₀-C₅ )(C₁-C₅ heterocyclyl), C(O)NR^(a)(C₀-C₅ alkyl)(C₃-C₆cycloalkyl), C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heteroaryl), C(O)NR

(C₁-C₅ alkyl)NR^(a)R^(b), C(O)NR^(a), (C₀-C₅ alkyl)(C₆ aryl), whereinsaid aryl, heterocyclyl, heteroaryl and cycloalkyl are optionallysubstituted by 1 to 5 substituents independently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl and C(O)(C₁-C₄ alkyl). In one example, R¹ is selected fromthe following:

wherein the wavy line represents the point of attachment to Formula I.

In one embodiment, R¹ is C₁-C₅ heteroaryl, optionally substituted by 1to 3 R

. In one example, R

is pyrazolyl or thiazolyl, optionally substituted by 1 or 2 R⁶, whereinR⁶ is C₁-C₆ alkyl or (C₀-C₆ alkyl)C₁-C₅ heterocyclyl, wherein said alkylis optionally substituted by 1 to 5 substituents independently selectedfrom OR

, NR^(c)R^(d), oxo and halo, and said heterocyclyl is optionallysubstituted by 1 to 5 substituents independently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl and C(O)(C₁-C₄ alkyl). In one example, said heterocyclyl ispyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,piperazinyl or moropholinyl. In one example, R¹ is selected from thefollowing:

wherein the wavy line represents the point of attachment to Formula I.

In one embodiment, R¹ is C₈-C₉ bicyclic heterocyclyl, optionallysubstituted by 1 to 5 R⁶. In one example, R¹ is indolinyl orisoindolinyl, optionally substituted by 1 to 3 R⁶. In one example, R¹ is3,3-dimethylindolin-2-only or 3,3-dimethylisoindolin-1-onyl.

In one embodiment, R¹ is C₁-C₅ heterocyclyl, optionally substituted by 1to 5 R⁶. In one example, R¹ is oxetanyl, optionally substituted by 1 to3 R⁶.

In one embodiment, R⁶ is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), halo, CN, CF₃, S(O)₁₋₂NR^(a)R^(b), C(O)R

, NR^(a)C(O)OR

, NR

S(O)₁₋₂NR^(b), (C₀-C₆ alkyl)C₁-C₅ heteroaryl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl, (C₀-C₆ alkyl)C₃-C₆ cycloalkyl, (C₀-C₆ alkyl)C₆-C₉ aryl,(C₀-C₆ alkyl)C(O)OR

, C(O)(C₀-C₆ alkyl)NR^(a)R^(b), C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl), C(O)NR^(a)(C₀-C₅alkyl)(C₃-C₆ cycloalkyl), C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heteroaryl),C(O)NR^(a)(C₁-C₅ alkyl)NR^(a)R^(b) or C(O)NR^(a)(C₁-C₅ alkyl)(C₆ aryl),wherein said alkyl, alkenyl and alkynyl are optionally substituted by 1to 5 substituents independently selected from OR^(a), NR^(c)R^(d), oxoand halo, and said aryl, heterocyclyl, heteroaryl and cycloalkyl areoptionally substituted by 1 to 5 substituents independently selectedfrom OR^(a), oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl, (C₀-C₆alkyl)C₁-C₅ heterocyclyl and C(O)(C₁-C₄ alkyl).

In one embodiment, R⁶ is independently C₁-C₆ alkyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), halo, CN, C₁-C₅ heteroaryl, C₄-C₅heterocyclyl, C₃-C₆ cycloalkyl, C₆ aryl, C(O)OR

, C(O)(C₀-C₅ alkyl)NR^(a)R^(b), C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl), C(O)NR^(a)(C₀-C₅ alkyl)(C₃-C₆cycloalkyl), C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heteroaryl), C(O)NR^(a)(C₁-C₅ alkyl)NR^(a)R^(b),C(O)NR^(a)(C₁-C₅ alkyl)(C₆ aryl), wherein said alkyl is optionallysubstituted by 1 to 5 substituents independently selected from OR

, NR^(c)R^(d), oxo and halo, and said aryl, heterocyclyl, heteroaryl andcycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl).

In one embodiment, R⁶ is C₄-C₅ heterocyclyl optionally substituted by 1to 5 substituents independently selected from OH, oxo, halo,CF₃,NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl).

In one embodiment, heterocyclyl is pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, 1,1-dioxotetrahydrothiophenyl, piperdinyl,piperizinyl, tetrahydropyranyl, thianyl, morpholinyl, pyridizinyl orhexahydrophrimidinyl.

In one embodiment, heterocyclyl is piperdinyl, piperizinyl ormorpholinyl.

In one embodiment, R⁶ is (C₀-C₆ alkyl)OR^(a) or (C₀-C₆alkyl)NR^(a)R^(b).

In one embodiment, R⁶ is (C₀-C₆ alkyl)OR

or (C₀-C₃ alkyl)NR^(a)R^(b).

In one embodiment, R⁶ is halo.

In one embodiment, R⁶, is F or Cl.

In one embodiment, R⁶ is S(O)₁₋₂NR^(a)R^(b). In one example, R⁶ isS(O)₂NH₂.

In one embodiment, R⁶ is NR

C(O)R^(b).

In one embodiment, R⁶ is NHCOCH₃.

In one embodiment, R⁶ is C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),C(O)NR

(C₀-C₅ alkyl)(C₃-C₆ cycloalkyl), C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heteroaryl), C(O)NR^(a)(C₁-C₅ alkyl)NR^(a)R^(b),C(O)NR^(a)(C₁-C₅ alkyl)(C₆ aryl), wherein said alkyl is optionallysubstituted by 1 to 5 substituents independently selected from OR

, NR^(c)R^(d), oxo and halo, and said aryl, heterocyclyl, heteroaryl andcycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl).

In one embodiment, R⁶ is C(O)OR

, C(O)(C₀-C₅ alkyl)(NR^(a)R^(b) or C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl,wherein said alkyl is optionally substituted by 1 to 5 substituentsindependently selected from OR

NR^(c)R^(d), oxo, and halo, and said aryl, heterocyclyl, heteroaryl andcycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl).

In one embodiment, R⁶ is independently C₁-C₆ alkyl, (C₀-C₆ alkyl),NR^(a)R^(b), (C₀-C₆ alkyl), C₁-C₅ heterocyclyl, (C₀-C₆ alkyl), C₃-C₆cycloalkyl, or C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl), wherein said alkylis optionally substituted by 1 to 5 substituents independently selectedfrom OR

, NR^(c)R^(d), oxo and halo, and said heterocyclyl and cycloalkyl areoptionally substituted by 1 to 5 substituents independently selectedfrom OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl and C(O)(C₁-C₄ alkyl). In one example, R⁶ is selected fromthe following:

wherein the wavy line represents the point of attachment in Formula I.

In one embodiment, R⁶ is (C₀-C⁶ alkyl)C₁-C₅ heteroaryl, optionallysubstituted by 1 to 5 substituents independently selected from OR^(a),halo, CF₃, NR^(c)R^(d) and C₁-C₄ alkyl. In one example, R⁷ is pyridinyl,optionally substituted by 1 to 5 substituents independently selectedfrom OR

, halo, CF₃, NR^(c)R^(d) and C₁-C₄ alkyl.

In one embodiment, R⁶ is selected from the following:

wherein the wavy line represents the point of attachment of Formula I.

In one embodiment, R³, R⁴ and R⁵ are independently H, CH₃, CF₃, or F.

In one embodiment, R³, R⁴ and R⁵ are independently H or F.

In one embodiment, R³, R⁴ and R⁵ are H.

In one embodiment, R³ is OCH₃.

In one embodiment, R² is phenyl, C₁-C

heteroaryl or C₃-C₅ heterocyclyl, wherein the phenyl, heteroaryl andheterocyclyl are optionally substituted by 1 to 5 R⁷.

In one embodiment, R² is phenyl optionally substituted by 1 to 5 R⁷.

In one embodiment, R² is phenyl optionally substituted by 1 to 3 R⁷.

In one embodiment, R² is phenyl optionally substituted by 2 R⁷.

In one embodiment, R² is phenyl or pyridinyl, optionally substituted by2 R

, wherein R⁷ is independently C₁-C₆ alkyl, OCF₃, OCH₃, NH₂, NO₂, CH₂NH₂,F, Cl, C(O)NR^(a)R^(b), NR^(a)C(O)R^(b), SO₂(C₁-C₃ alkyl),SO₂NR^(a)R^(b), CN, CF₃, OCF₃, C(O)R

, C(O)OR

, (C₀-C₆ alkyl)C₁-C₅ heterocyclyl, C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclylor C(O)NR

(C₀-C₆ alkyl)C₁-C₅ heterocyclyl, wherein said heterocyclyl is optionallysubstituted by C₁-C₄ alkyl. In one example, R² is selected from:

wherein the wavy line represents the point of attachment of Formula I.

In one embodiment, R² is pyrazolyl, optionally substituted by 1 or 2 R

, wherein R⁷ is independently R⁷ is independently C₁-C₆ alkyl, (C₀-C₆alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), (C₀-C₆ alkyl)(C₆-C₉ aryl), halo, (C₀-C₆alkyl)C₁-C₅ heteroaryl, (C₀-C₆ alkyl)C₁-C₅ heterocyclyl or (C₀-C₆alkyl)C₃-C₆ cycloalkyl, wherein said alkyl, is optionally substituted by1 to 5 substituents independently selected from oxo, NR^(a)R^(b),OR^(a), and halo, and said aryl, heteroaryl, heterocyclyl and cycloalkylare optionally substituted by 1 to 5 substituents independently selectedfrom OR

, halo, CF₃, NR^(c)R^(d) and C₁-C₄ alkyl. In one example, R² is selectedfrom

wherein the wavy line represents the point of attachment in Formula I.

In one embodiment, R² is phenyl optionally substituted by 1 R⁷.

In one embodiment, R⁷ is independently C₁-C₆ alkyl, (C₀-C₆ alkyl)OR^(a),(C₀-C₆ alkyl)NR^(a)R^(b), (C₀-C₆ alkyl)(C₆-C₉ aryl), halo,C(O)NR^(a)R^(b), NR^(a)C(O)R^(b), SO₂(C₁-C₆ alkyl), SO₂NR_(a)R^(b), CN,nitro, wherein said alkyl is optionally substituted by 1 to 5substituents independently selected from oxo and halo, and said and saidaryl is optionally substituted by 1 to 5 substituents independentlyselected from OR^(a), halo, CF₃, NR^(c)R^(d) and C₁-C₄ alkyl.

In one embodiment, R⁷ is independently C₁-C₄ alkyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), halo, NR^(a)C(O)R^(b), SO₂(C₁-C₆ alkyl),SO₂NR^(a)R^(b), CN or nitro.

In one embodiment, R⁷ is independently C₃-C₆ cycloalkyl.

In one embodiment, R⁷ is independently NH₂, OCH₃, CH₃, CH₂CH₃,CH(CH₃)₂), NO₂, OCF₃, S(O)₂N(CH₃)₂, S(O)NH(CH(CH₃)₂), S(O)₂NH(C(CH₃)₂),CN, CF₃, F, Cl, NHC(O)CH₃ or S(O)₂CH₃.

In one embodiment, R⁷ is independently NH₂, OCH₃, CH₃, CH₂CH₃,CH(CH₃)₂), NO₂, OCF₃, S(O)₂N(CH₃)₂, S(O)₂NH(CH(CH₃)₂), S(O)₂NH(C(CH₃)₃),CN, CF₃, F, Cl, NHC(O)CH₃, S(O)₂CH₃, CO₂H, S(O)CH₃, cyclopentyl,1-hydroxyethyl, 1-aminoethyl or CH₂CF₃.

In one embodiment, R² is C₁-C₉ heteroaryl optionally substituted by 1 to5 R⁷.

In one embodiment, C₁-C₉ heteroaryl is pyridinyl, imidazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, trazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinoxalinyl, quinoxalinyl, naphthyridinyl or furopyridinyl, each ofwhich is optionally substituted by 1 to 5 R⁶.

In one embodiment, R

is pyridinyl or pyrazolyl optionally substituted by 1 to 5 R⁷.

In one embodiment, R² is pyridinyl or pyrazolyl optionally substitutedby 1 to 3 R⁷.

In one embodiment, R² is pyridinyl or pyrazolyl optionally substitutedby 1 R⁷.

In one embodiment, R⁷ is independently CH₃, CH₂(phenyl), CH₂CH(CH₃)₂, orCF₃.

In one embodiment, R² is C₃-C₅ heterocyclyl optionally substituted by 1to 5 R⁷.

In one embodiment, R² is piperdinyl, morpholinyl or piperizinyloptionally substituted by 1 to 5 R⁷.

In one embodiment, R² is piperdinyl, morpholinyl or piperizinyloptionally substituted by 1 to 3 R⁷.

In one embodiment, R² is piperdinyl, morpholinyl or piperizinyloptionally substituted by 2 R⁷.

In one embodiment, R² is piperdinyl, morpholinyl or piperizinyloptionally substituted by 1 R⁷.

In one embodiment, R⁷ is independently CH₃, CH₂CH₃, OH or OCH₃.

In one embodiment, R¹ is phenyl, optionally substituted by 1 to 5 R⁶;and R² is phenyl, optionally substituted by 1 to 5 R⁷.

In one embodiment, R¹ is phenyl, optionally substituted by 1 to 5 R⁶;and R² is heterocyclyl, optionally substituted by 1 to 5 R⁷.

In one embodiment, heterocyclyl is piperidinyl, morpholinyl orpiperizinyl.

In one embodiment, R¹ is pyridyl, optionally substituted by 1 to 4 R⁶;and R² is phenyl, optionally substituted by 1 to 5 R⁷.

In one embodiment, R¹ is pyridyl, optionally substituted by 1 to 4 R⁶;and R² is heterocyclyl, optionally substituted by 1 to 5 R⁷.

In one embodiment, heterocyclyl is piperidinyl, morpholinyl orpiperizinyl.

In one embodiment, R¹ is phenyl, optionally substituted by 1 to 5 R⁶;and R² is phenyl, optionally substituted by 1 to 4 R⁷.

In one embodiment, R¹ is pyridyl, optionally substituted by 1 to 4 R⁶;and R² is phenyl, optionally substituted by 1 to 4 R⁷.

In one embodiment, R¹ is phenyl or pyridinyl, optionally substituted by1 to 3 R⁶, wherein R⁶ is independently C₁-C₃ alkyl, halo, CF₃, or C(O)OR

; and R² is phenyl or pyridinyl, optionally substituted by 2 R⁷, whereinR⁷ is independently C₁-C₆ alkyl, OCF₃, OCH₃, NH₂, CH₂NH₂, F, Cl,C(O)NR^(a)N^(b), NR

C(O)R^(b), SO₂(C₁-C₃alkyl), SO₂NR^(a)R^(b), CN, CF₃, OCF₃, C(O)R

, C(O)OR

.

Another embodiment includes a compound selected from:

Another embodiment includes compounds of Formula I, selected from thecompounds of Examples 1-312.

Another embodiment includes a compound of Formula I that has K, and/orEC₅₀ that is at least 15 fold, alternatively 10 fold, or 5 fold or moreselective in inhibiting one Janus kinase activity over inhibiting eachof the other Janus kinase activities.

The compounds of Formula I may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula I, includingbut not limited to: diastereomers, enantiomers, and atropisomers as wellas mixtures thereof such as racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula I incorporatesa double bond or a fused ring, both the cis- and trans-forms, as well asmixtures, are embraced within the scope of the invention. Both thesingle positional isomers and mixture of positional isomers, e.g.,resulting from the N-oxidation of the pyrimidinyl and pyrrozolyl rings,or the E and Z forms of compounds of Formula I (for example oximemoieties), are also within the scope of the present invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the invention, asdefined by the claims, embrace both solvated and unsolvated forms.

In an embodiment, compounds of Formula I may exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention, as defined by the claims. The “tautomer” or “tautomericform” refers to structural isomers of different energies which areinterconvertible via a low energy barrier. For example, proton tautomers(also known as prototropic tautomers) include interconversions viamigration of a proton, such as keto-enol and imine-enamineisomerizations. Valence tautomers include interconversions byreorganization of some of the bonding electrons.

The present invention also embraces isotopically-labeled compounds ofFormula I, which are identical to those recited herein, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. All isotopes of any particular atom or element as specifiedare contemplated within the scope of the invention. Exemplary isotopesthat can be incorporated into compounds of Formula I include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,

C, ¹³N, ¹⁵N, ¹⁵O,

O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Certainisotopically-labeled compounds of Formula I (e.g., those labeled with ³Hand ¹⁴C) are useful in compound and/or substrate tissue distributionassay. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes are usefulfor their case of preparation and detectability. Further, substitutionwith heavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements) and hencemay be preferred in some circumstances. Positron emitting isotopes suchas ¹⁵O, ¹³N, ¹¹C, and

F are useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of FormulaI can generally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples herein below, bysubstituting an isotopicallly labeled reagent for a non-isotopicallylabeled reagent.

Synthesis of Triazolopyridine JAK Inhibitor Compounds

Compounds of Formula I may be synthesized by synthetic routes describedherein. In certain embodiments, processes well-known in the chemicalarts can be used, in addition to, or in light of, the descriptioncontained herein. The starting materials are generally available fromcommercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or arereadily prepared using methods well known to those skilled in the art(e.g., prepared by methods generally described in Louis F. Fieser andMary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y.(1967-1999 ed.), Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplements (also available viathe Beilstein online database)), or Comprehensive HeterocyclicChemistry, Editors Katrizky and Rees, Pergamon Press, 1984. Methods fortriazolopyridine synthesis are also disclosed in: WO 02/38572 and WO2006/038116.

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds of Formula I. Libraries of compounds of Formula I may beprepared by a combinatorial ‘split and mix’ approach or by multipleparallel syntheses using either solution phase or solid phase chemistry,by procedures known to those skilled in the art. Thus according to afurther aspect of the invention there is provided a compound librarycomprising at lease 2 compounds of Formula I, enantiomer, diasteriomers,tautomers or pharmaceutically acceptable salts thereof.

For illustrative purposes, reaction schemes 1-6 depicted below provideroutes for synthesizing the compounds of the present invention as willas key intermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In the preparation of compounds of the present invention, protection ofremote functionality (e.g., primary or secondary amine) of intermediatesmay be necessary. The need for such protection will may depending on thenature of the remote functionality and the conditions of the preparationmethods. Suitable amino-protecting groups (NH-Pg) include acetyl,trifluroracetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl, (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

Compounds of the invention may be prepared from readily availablestarting materials using the general methods illustrated herein.

For example, compounds of Formula I can be synthesized as shown inReaction Scheme 1. A common protected intermediate 5, which is availablefrom 2-amino-3-bromopyridine (2), can be subjected topalladium-catalyzed coupling reactions such as the Suzuki reaction withboronic acids or boronate esters to form compounds of Formula 6 afterprotective group removal. Palladium-catalyzed amination of aryl orheteroaryl halides with triazolopyridinamine 6 provides compounds ofFormula 1a. Palladium-catalyzed amination of methoxycarbonyl substitutedphenyl halides or methoxycarbonyl substituted heteroaryl halides 7 withtriazolopyridinamine 6 provides compounds of Formula 1b. Hydrolysis ofthe corresponding methyl esters 1b affords carboxylic acids 1c, whichcan be subjected to standard amide formation methods to yield amides 1d.

It will be appreciated that where appropriate functional groups exist,compounds of various formulae or any intermediates used in theirpreparation may be further derivatized by one or more standard syntheticmethods employing condensation, substitution, oxidation, reduction, orcleavage reactions. Particular substitution approaches includeconventional alkylation, arylation, heteroarylation, acylation,sulfonylation, halogenation, nitration, formylation and couplingprocedures.

In a further example, primary amine or secondary amine groups may beconverted into amide groups (—NHCOR′ or —NRCOR′) by acylation. Acylationmay be achieved by reaction with an appropriate acid chloride in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dichloromethane, or by reaction with an appropriated carboxylic acidin the presence of a suitable coupling agent such HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in a suitable solvent such as dichloromethane.Similarly, amine groups may be converted into sulphonamide groups(—NHSO₂R′ or —NR″SO₂R′) groups by reaction with an appropriate sulphonylchloride in the presence of a suitable base, such as triethylamine, in asuitable solvent such as dichloromethane. Primary or secondary aminegroups can be converted into urea groups (—NHCONR′R″ or —NRCONR′R″) byreaction with an appropriate isocyanate in the presence of a suitablebase such as triethylamine, in a suitable solvent, such asdichloromethane.

An amine (—NH₂) may be obtained by reduction of a nitro (—NO₂) group,for example by catalytic hydrogenation, using for example hydrogen inthe presence of a metal catalyst, for example palladium on a supportsuch as carbon in a solvent such as ethyl acetate or an alcohol e.g.methanol. Alternatively, the transformation may be carried out bychemical reduction using for example a metal, e.g. tin or iron, in thepresence of an acid such as hydrochloric acid.

In a further example, amine (—CH₂NH₂) groups may be obtained byreduction of nitriles (—CH), for example by catalytic hydrogenationusing for example hydrogen in the presence of a metal catalyst, forexample palladium on a support such as carbon, or Raney nickel, in asolvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, atan appropriate temperature, for example from about −78° C. to the refluxtemperature of the solvent.

In a further example, amine (—NH₂) groups may be obtained fromcarboxylic acid groups (—CO₂H) by conversion to the corresponding acylazide (—CON₃), Curtius rearrangement and hydrolysis of the resultantisocyanate (—N═C═O).

Aldehyde groups (—CHO) may be converted to amine groups (—CH₂NR′R″)) byreductive amination employing an amine and a borohydride, for examplesodium triacetoxyborohydride or sodium cyanoborohydride, in a solventsuch as a halogenated hydrocarbon, for example dichloromethane, or analcohol such as ethanol, where necessary in the presence of an acid suchas acetic acid at around ambient temperature.

In a further example, aldehyde groups may be converted into alkenylgroups (—CH═CHR′) by the use of a Wittig or Wadsworth-Emmons reactionusing an appropriate phosphorane or phosphonate under standardconditions known to those skilled in the art.

Aldehyde groups may be obtained by reduction of ester groups (such as—CO₂Et) or nitriles (—CH) using diisobutylaluminium hydride in asuitable solvent such as toluene. Alternatively, aldehyde groups may beobtained by the oxidation of alcohol groups using any suitable oxidisingagent know to those skilled in the art.

Ester groups (—CO₂R′) may be converted into the corresponding acid group(—CO₂H) by acid- or base-catalyzed hydrolysis depending on the nature ofR. If R is t-butyl, acid-catalysed hydrolysis can be achieved forexample by treatment with an organic acid such as trifluoroacetic acidin an aqueous solvent, or by treatment with an inorganic acid such ashydrochloric acid in an aqueous solvent.

Carboxylic acid groups (—CH₂H) may be converted into amides (CONHR′ or—CONR′R″) by reaction with an appropriate amine in the presence of asuitable coupling agent, such as HATU, in a suitable solvent such asdichloromethane.

In a further example, carboxylic acids may be homologated by one carbon(i.e. —CO₂H to —CH₂CO₂H) by conversion to the corresponding acidchloride (—COCl) followed by Arndt-Eistert synthesis.

In a further example, —OH groups may be generated from the correspondingester (e.g. —CO₂R′), or aldehyde (—CHO) by reduction, using for examplea complex metal hydride such as lithium aluminium hydride in diethylether or tetrahydrofuran, or sodium borohydride in a solvent such asmethanol. Alternatively, an alcohol may be prepared by reduction of thecorresponding acid (—CO₂H), using for example lithium aluminium hydridein a solvent such as tetrahydrofuran, or by using borane in a solventsuch as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as halogenatoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxygroup using conditions known to those skilled in the art. For example,an alcohol may be reacted with thioyl chloride in a halogenatedhydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.A base (e.g. triethylamine) may also be used in the reaction.

In another example, alcohol, phenol or amide groups may be alkylated bycoupling a phenol or amide with an alcohol in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl—, diisopropyl, ordimethylazodicarboxylate. Alternatively alkylation may be achieved bydeprotonation using a suitable base e.g. sodium hydride followed bysubsequent addition of an alkylating agent, such as alkyl halide.

Aromatic halogen substituents in the compounds may be subjected tohalogen-metal exchange by treatment with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g. around −78° C., in a solvent such as tetrahydrofuran,and then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing N,N-dimethylformamide as the electrophile. Aromatic halogensubstituents may alternatively be subjected to metal (e.g. palladium orcopper) catalyzed reactions, to introduce, for example, acid, ester,cyano, amide, aryl, heteroaryl, alkenyl, alkynyl, thio- or aminosubstituents. Suitable procedures which may be employed include thosedescribed by Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogen substituents may also undergo nucleophilic displacementfollowing reaction with an appropriate nucleophile such as an amine oran alcohol. Advantageously, such a reaction may be carried out atelevated temperature in the presence of microwave irradiation.

Methods of Separation

In each of the exemplary Schemes it may be advantageous to separatereaction products from one another and/or from starting material. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents, such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiasterioisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diasteroisomers and converting (e.g., hydrolyzing) theindividual diasteroisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropiosomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g. an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S., Stereochemistry of OrganicCompounds, 113(3):283-302 (1975)). Racemic mixtures of chiral compoundsof the invention can be separated and isolated by any suitable method,including: (1) formation of ionic, diasteromeric salts with chiralcompounds and separation by fractional crystallization or other methods,(2) formation of diasteriomeric compounds with chiral derivatizingreagents, separation of the diastereomers, and conversion to the purestereoisomers, and (3) separation of the substantially pure or enrichedstereoisomers directly under chiral conditions. See: DrugStereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reaction of enantiomerically purechiral bases such as brucine, quinine, ephedrine, strychnine,α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetriccompounds bearing acidic functionality, such as carboxylic acid andsulfonic acid. The diasteromeric salts may be induced to separate byfractional crystallization or ionic chromatography. For separation ofthe optical isomers of amino compounds, addition of chiral carboxylic orsulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelicacid, or lactic acid can result in formulation of the diastereomericsalts.

Alternatively, the substrate to be resolved is reacted with oneenantiomer of a chiral compound to form a diastereomeric pair (Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons,Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral ester, such as a menthyl ester, e.g. (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem.47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). Bymethod (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (Chiral LiquidChromatography W. J. Lough, Ed., Chapman and Hall, New York, (1989);Okamoto, J. of Chromatogr. 513:375-378 (1990)). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Positional isomers, for example E and Z forms, of compounds of FormulaI, and intermediates for their synthesis, may be observed bycharacterization methods such as NMR and analytical HPLC. For certaincompounds where the energy barrier for interconversion is sufficientlyhigh, the E and Z isomers may be separated, for example by preparatoryHPLC.

Biological Evaluation

Previous studies have known that the isolated kinase domains of humanJAK1, JAK2, JAK3 or TYK2 phosphorylate peptide substrates in in vitrokinase assays (Saltzman et al., Biochem. Biophys. Res. Commun.246:627-633 (2004)). The catalytically active kinase domain of humanJAK1, JAK2, JAK3 or TYK2 was purified from extracts of SF9 insect cellsinfected with a recombinant baculovirus expression vector encoding thehuman JAK1, JAK2, JAK3 or TYK2 kinase domains (JAK1 amino acid residuesN852-D1154 according to the numbering of GenBank sequence accessionnumber P23458, JAK2 amino acid residues D812-G1132 according to thenumbering of GenBank sequence accession number NP₁₃ 004963.1; JAK3 aminoacid residues S783-S1124 according to the numbering of GenBank sequenceaccession number P52333, and TYK2 amino acid residues N873-C1187according to the numbering of GenBank sequence accession number P29597).The activity of the JAK1, JAK2, JAK3 or TYK2 kinase domains can bemeasured by a number of direct and indirect methods, includingquantification of phosphorylation of peptide substrates derived from thehuman JAK3 protein (Saltzman et al., Biochem. Biophys. Res. Commun.246:627-633 (2004)). The activity of the JAK1, JAK2, JAK3 or TYK2 kinasedomains was measured in vitro by monitoring phosphorylation of JAK3derived peptides using the Caliper LabChip technology (see Examples).

The compounds of the present invention are tested for their capacity toinhibit a Janus kinase activity and activation (primary assays) and fortheir biological effects on growing cells (secondary assays) asdescribed herein. The compounds having IC₅₀ of less than 10 μM(preferably less than 5 μM, more preferably less than 1 μM, mostpreferably less than 0.5 μM) in the appropriate Janus kinase activityand activation assay (see Examples A and B), and EC₅₀ of less than 20 μM(preferably less than 10 μM, more preferable less than 5 μM, mostpreferably less than 1 μM) in the appropriate cellular assays (seeExample C) are useful as Janus kinase inhibitors.

Administration of Triazolopyridine Compounds

Another embodiment includes a method of treating or lessening theseverity of a disease or condition responsive to the inhibition of oneof more Janus kinase activity, selected from JAK1, JAK2, JAK3 and TYK2,in a patient. The method includes administering to the patient atherapeutically effective amount of a compound of Formula I.

Another embodiment includes a method of treating or lessening theseverity of a disease or condition responsive to the inhibition of JAK2kinase activity in a patient. The method includes the step ofadministering to a patient a therapeutically effective amount of acompound of Formula I.

In one embodiment, the disease or condition is cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer'sdisease, cystic fibrosis, viral disease, autoimmune diseases,atherosclerosis, restenosis, psoriasis, allergic disorders,inflammation, neurological disorders, a hormone-related disease,conditions associated with organ transplantation, immunodeficiencydisorders, destructive bone disorders, proliferative disorders,infectious disease, conditions associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, CNS disorder or amyeloproliferative disorder.

In one embodiment, the disease or condition is cancer.

In one embodiment, the disease is a myeloproliferative disorder.

In one embodiment, the myeloproliferative disorder is polycythemia vera,essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia(CML).

In one embodiment, the cancer is breast, ovary, cervix, prostate,testis, penile, genitourinary tract, seminoma, esophagus, larynx,gastric, stomach, gastrointestinal, skin, keratoacanthoma, follicularcarcinoma, melanoma, lung, small cell lung carcinoma, non-small celllung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of thelung, colon, pancreas, thyroid, papillary, bladder, liver, biliarypassage, kidney, bone, myeloid disorders, lymphoid disorders, hairycells buccal cavity and pharynx (oral), lip, tongue, mouth, salivarygland, pharynx, small intestine, colon, rectum, anal, renal, prostate,vulval, thyroid, large intestine, endometrial, uterine, brain, centralnervous system, cancer of the peritoneum, hepatocellular cancer, headcancer, neck cancer, Hodgkin's or leukemia.

In one embodiment, the cardiovascular disease is restenosis,cardiomegaly, atherosclerosis, myocardial infarction or congestive heartfailure.

In one embodiment, the neurodegenerative disease is Alzheimer's disease,Parkinson's disease, amyotrohpic lateral sclerosis, Huntington'sdisease, and cerebral ischemia, and neurodegenerative disease caused bytraumatic injury, glutamate neurotoxicity or hypoxia.

In one embodiment, the inflammatory disease is rheumatoid arthritis,psoriasis, contact dermatitis or delayed hypersensitivity reactions.

In one embodiment, the inflammatory disease is inflammatory boweldisease,

In one embodiment, the autoimmune disease is lupus or multiplesclerosis.

Evaluation of drug-induced immunosuppression by the compounds of theinvention may be performed using in vivo functional tests, such asrodent models of induced arthritis and therapeutic or prophylactictreatment to assess disease score, T cell-dependent antibody response(TDAR), and delayed-type hypersensitivity (DTH). Other in vivo systemsincluding murine models of host defense against infections or tumorresistance (Burleson G R, Dean J H, and Munson A E. Methods inImmunotoxicology, Vol. 1. Wiley-Liss, New York, 1995) may be consideredto elucidate the nature of mechanisms of observed immunosuppression. Thein vivo test systems can be complemented by well-established in vitro orex vivo functional assays for the assessment of immune competence. Theseassays may comprise B or T cell proliferation in response to mitogens orspecific antigens, measurement of signaling through one or more of theJanus kinase pathways in B or T cells or immortalized B or T cell lines,measurement of cell surface markers in response to B or T cellsignaling, natural killer (NK) cell activity, mast cell activity, mastcell degranulation, macrophage phagocytosis or kill activity, andneutrophil oxidative burst and/or chemotaxis. In each of these testsdetermination of cytokine production by particular effector cells (e.g.,lymphocytes, NK, monocytes/macrophages, neutrohils) may be included. Thein vitro and ex vivo assays can be applied in both preclinical andclinical testing using lymphoid tissues and/or peripheral blood (House RV. “Theory and practice of cytokine assessment in immunotoxicology”(1990) Methods 19:17-27; Hubbard A K. “Effects of xenobiotics onmacrophage function: evaluation in vitro” (1999) Methods: 19:8-16;Lebree H, et al (2001) Toxicology 158:25-29).

Collagen-Induced Arthritis (CIA) 6-week detailed study using anautoimmune mechanism to mimic human arthritis; rat and mouse models(Example 68). Collagen-Induced arthritis (CIA) is one of the mostcommonly used animal models of human rheumatoid arthritis (RA). Jointinflammation, which develops in animals with CIA, strongly resemblesinflammation observed in patients with RA. Blocking tumor necrosisfactor (TNF) is an efficacious treatment of CIA, just as it is a highlyefficacious therapy in treatment of RA patients. CIA is mediated by bothT-cells and antibodies (B-cells). Macrophages are believed to play animportant role in mediating tissue damage during disease development.CIA is induced by immunizing animals with collagen emulsified inComplete Freund's Adjuvant (CFA). It is most commonly induced in theDBA/1 mouse strain, but the disease can also be induced in Lewis rats.

There is good evidence that B-cells play a key role in the pathogenesisof autoimmune and/or inflammatory disease. Protein-based therapeuticsthat deplete B cells such as Rituxan are effective againstautoantibody-driven inflammatory diseases such as rheumatoid arthritis(Rastetter et al. (2004) Annu Rev Med 55:477). CD69 is the earlyactivation marker in leukocytes including T cells, thymocytes, B cells,NK cells, neutrophils, and eosinophils. The CD69 human whole blood assay(Example 69) determines the ability of compounds to inhibit theproduction of CD69 by B lymphocytes in human whole blood activated bycrosslinking surface IgM with goat F(ab′)2 anti-human IgM.

The T-cell Dependent Antibody Response (TDAR) is a predictive assay forimmune function testing when potential immunotoxic effects of compoundsneed to be studied. The IgM-Plaque Forming Cell (PFC) assay, using SheepRed Blood Cells (SRBC) as the antigen, is currently a widely acceptedand validated standard test. TRDAR has proven to be a highly predictableassay for adult exposure immunotoxicity detection in mice based on theUS National Toxicology Program (NTP) database (M. J. Luster et al (1992)Fundam. Appl. Toxicol. 18:200-210). The utility of this assay stems fromthe fact that it is a holistic measurement involving several importantcomponents of an immune response. A TDAR is dependent on functions ofthe following cellular compartments: (1) antigen-presenting cells, suchas macrophages or dendritic cells; (2) T-helper cells, which arecritical players in the genesis of the response, as well as in isotypeswitching; and (3) B-cells, which are the ultimate effector cells andare responsible for antibody production. Chemically-induced changes inany one compartment can cause significant changes in the overall TDAR(M. P. Holsapple In: G. R. Burleson, J. H. Dean and A. E. Munson,Editors, Modern Methods in Immunotoxicology, Volume 1, Wiley-LissPublishers, New York, N.Y. (1995), pp. 71-108). Usually, this assay isperformed either as an ELISA for measurement of soluble antibody (R. J.Smialowizc et al (2001) Toxicol. Sci. 61:164-175) or as a plaque (orantibody) forming cell assay (L. Guo et al (2002) Toxicol. Appl.Pharmacol. 181:219-227) to detect plasma cells secreting antigenspecific antibodies. The antigen of choice is either whole cells (e.g.sheep erythrocytes) or soluble protein antigens (T. Miller et al (1998)Toxicol. Sci. 42:129-135).

A compound of Formula I may be administered by any route appropriate tothe disease or condition to be treated. Suitable routes include oral,parenteral (including subcutaneous, intramuscular, intravenous,intraaterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary, and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the preferred route may vary with for example thecondition of the recipient. Where the compound of Formula I isadministered orally, it may be formulated as a pill, capsule, tablet,etc. with a pharmaceutically acceptable carrier or excipient. Where thecompound of Formula I is administered parenterally, it may be formulatedwith a pharmaceutically acceptable parenteral vehicle and in a unitdosage injectable form, as detailed below.

A dose to treat human patients may range from about 10 mg to about 1000mg of a compound of Formula I. A typical dose may be about 100 mg toabout 300 mg of a compound of Formula I. A dose may be administered oncea day (QD), twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Another embodiment of the invention aspect of this invention provides acompound of this invention for use as a medicament in the treatment ofthe diseases or conditions described herein in a mammal, for example, ahuman, suffering from such disease or condition. Also provided is theuse of a compound of this invention in the preparation of a medicamentfor the treatment of the diseases and conditions described herein in awarm-blooded animal, such as a mammal, for example a human, sufferingfrom such disorder.

Pharmaceutical Formulations of Triazolopyridine Compounds

Another embodiment includes a pharmaceutical composition that includes acompound of Formula I and a pharmaceutically acceptable carrier,adjuvant or vehicle.

In one embodiment, the pharmaceutical composition also includes anadditional therapeutic agent selected from an anti-proliferative agent,and anti-inflammatory agent, an immunomodulatory agent, a neurotropicfactor, an agent for treating cardiovascular disease, an agent fortreating liver disease, and anti-viral agent, an agent for treatingblood disorders, an agent for treating diabetes, or an agent fortreating immunodeficiency disorders.

In another embodiment, a compound of Formula I is present in apharmaceutical formulation in an amount to detectably inhibit one ormore of a Janus kinase activity, selected from JAK1, JAK2, JAK3 andTYK2, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

In one embodiment, a compound of Formula I is present in apharmaceutical formulation in an amount to detectably inhibit JAK2kinase activity and a pharmaceutically acceptable carrier, adjuvant orvehicle.

In one embodiment, a compound of Formula I is present in apharmaceutical formulation in an amount to detectably inhibit JAK2kinase activity and is a least 10 fold or more selective in inhibitingJAK2 kinase activity over inhibiting each of JAK1, JAK3 and Tyk2activity.

In one embodiment, a compound of formula I is present in apharmaceutical formulation in an amount to detectable inhibit one of aJanus kinase activity and is at least 15 fold, alternatively 10 fold, or5 fold or more selective in inhibiting one such Janus kinase activityover inhibiting each of the other Janus kinase activity.

In one embodiment, a compound of Formula I is present in apharmaceutical formulation in an amount to detectably inhibit a Januskinase activity and is a least 15 fold, alternatively 10 fold, or 5 foldor more selective in inhibiting one Janus kinase activity overinhibiting each of the other JAK1, JAK2, JAK3 and/or Tyk2 activity.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water, and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected base on solvents recognized by persons skilled in theart as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweetners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound, such as acomplex with a cyclodextrin derivative or other known complexationagent) is dissolved in a suitable solvent in the presence of one or moreof the excipients described above. The compound of the present inventionis typically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to enable patient compliancewith the prescribed program.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical, formulations of a compound of Formula I may be preparedfor various routes and types of administration. A compound of Formula Ihaving the desired degree of purity is optionally mixed withpharmaceutically acceptable diluents, carriers, excipients orstabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition,Osol, A. Ed.), in the form of a lyophilized formulation, milled powder,or an aqueous solution. Formulation may be conducted by mixing atambient temperature at the appropriate pH, and at the desired degree ofpurity, with physiologically acceptable carriers, i.e., carriers thatare non-toxic to recipients at the dosages and concentrations employed.The pH of the formulation depends mainly on the particular use and theconcentration of compound, but may range from about 3 to about 8.Formulation in an acetate buffer at pH 5 is a suitable embodiment.

The inhibitory compound for use herein is preferably sterile. Thecompound ordinarily will be stored as a solid composition, althoughlyophilized formulations or aqueous solutions are acceptable.

The pharmaceutical compositions of the invention will be formulated,dosed, and administered in a fashion, i.e. amounts, concentrations,schedules, course, vehicles, and route of administration, consistentwith good medical practice. Factors for consideration in this contextinclude the particular disorder being treated, the particular mammalbeing treated, the clinical condition of the individual patient, thecause of the disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. The “therapeutically effective amount”of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to prevent,ameliorate, or treat the disorder. Such amount is preferably below theamount that is toxic to the host.

As a general proposition, the initial pharmaceutically effective amountof the inhibitor administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient bodyweight per day, with the typical initial range of compound used being0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients, and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid and methionine; preservatives (suchas octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parbens such as methyl or propyl parben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides, and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose ofgelatin-microcapsules and poly-(methylmethacrylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsion, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing a compound of Formula I, which matricesare in the form of shaped articles, e.g. films, or microcapsules.Examples of sustained-release matrices include polyester, hydrogels (forexample, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acidand gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid.

The formulations to be used for in vivo administration must be sterile,which is readily accomplished by filtration through sterile filtrationmembranes.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Eaton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one of more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of formula I suitable for oral administrationmay be prepared as discrete units such as pills, capsules, cachets ortablets each containing a predetermined amount of the compound ofFormula I.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g. gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof a compound of Formula I intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,calcium or sodium phosphate; granulating and disintegrating agents, suchas maize starch, or alginic acid; binding agents, such as starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to delay disintegration andadsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl disterarate alone or with a wax may beemployed.

For infections of the eye or other external tissues e.g. mouth and skin,the formulations are preferably applied as a topical ointment or creamcontaining the active ingredient(s) in an amount of, for example, 0.075to 20% w/w. When formulated in an ointment, the active ingredients maybe employed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base.

If desired, the aqueous phase of the cream base may include a polyhydricalcohol, i.e. an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400) and mixtures thereof. Thetopical formulations may desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sufoxide and related analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emusifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations. Emulgents and emulsionstabilizers suitable for use in the formulation of the invention includeTween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristylalcohol, glyceryl mono-stearate and sodium lauryl sulfate.

Aqueous suspensions of the invention contain the active material inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia, and dispersing or wetting agents such as anaturally occurring phosphatide (e.g., lecthin), a condensation productof an alkyl oxide (e.g. ethylene oxide, propylene oxide) with a fattyacid (e.g., polyoxyethylene stearate), a condensation product ofethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

The pharmaceutical composition of a compound of Formula I may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in a 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferable present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 and 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alvelolar sacs. Suitableformulation suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis of HIV infections as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or as appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising atlease one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

A compound of Formula I may be combined in a pharmaceutical combinationformulation, or dosing regimen as combination therapy, with a secondcompound that has anti-hyperproliferative or chemotherapeuticproperties, that is useful for treating a disease or disorder responsiveto the inhibition of a JAK kinase, for example a hyperproliferativedisorder (e.g. cancer), or that is useful in treating another disordernamed herein. The second compound of the pharmaceutical combinationformulation or dosing regimen preferable has complementary activities toa compound of Formula I of the combination such that they do notadversely affect each other. Such molecules are suitable present incombination in amounts that are effective for the purpose intended.

In another embodiment, a compound of Formula I may be employed alone orin combination with other therapeutic agents for the treatment of adisease of disorder described herein, such as an immunologic disorder(e.g. psoriasis or inflammation). In certain embodiments, a compound ofFormula I is combined in a pharmaceutical combination formulation, ordosing regimen as combination therapy, with a second therapeuticcompound that has anti-inflammatory or that is useful for treating aninflammation, immune-response disorder. The second therapeutic agent maybe a NSAID or other anti-inflammatory agent. In one embodiment, acomposition of this invention comprises a compound of Formula I, or astereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof, in combination witha therapeutic agent such as an NSAID.

Another embodiment, therefore, includes a method of treating orlessening the severity of a disease or condition responsive to theinhibition of JAK2 kinase activity in a patient, comprisingadministering to said patient a therapeutically effective amount of acompound of Formula I, and further comprising, administering a secondchemotherapeutic agent.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; (3) by some otherregimen. When delivered in alternation therapy, a synergistic effect maybe attained when the compounds are administered or deliveredsequentially, e.g. by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e. serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

Metabolites of the Triazolopyridine Compounds

Another embodiment includes in vivo metabolic products of anadministered compound of Formula I. Such products may result for examplefrom the oxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g. ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g. greater thenabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g. byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well-known tothose skilled in the art. The conversion products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of a compound of formula I.

Articles of Manufacture

Another embodiment includes a kit for treating a disease or disorderresponsive to the inhibition of a JAK kinase. The kit includes:

-   (a) a first pharmaceutical composition comprising a compound of    Formula I; and-   (b) instructions for use.

In another embodiment, the kit further includes:

-   (c) a second pharmaceutical composition which includes a    chemotherapeutic agent.

In one embodiment, the instructions include instructions for thesimultaneous, sequential or separate administration of said first andsecond pharmaceutical compositions to a patient in need thereof.

In one embodiment, the first and second compositions are contained inseparate containers.

In one embodiment, the first and second compositions are contained inthe same container.

Containers for use include, for example, bottle, vials, syringes,blister pack, etc. The containers may be formed from a variety ofmaterials such as glass or plastic. The container includes a compound ofFormula I or formulation thereof which is effective for treating thecondition and may have a sterile access port (for example the containermay be an intravenous solution bag or a vial having a stopper pierceableby a hypodermic injection needle). The container includes a compositionat least one compound of Formula I. The label or package insertindicates that the composition is used for treating the condition ofchoice, such as cancer. In one embodiment, the label or package insertsindicates that the composition comprising the compound of Formula I canbe used to treat a disorder. In addition, the label or package insertmay indicate that the patient to be treated is one having a disordercharacterized by overactive or irregular kinase activity. The label orpackage insert may also indicate that the composition can be used totreat other disorders.

The article of manufacture may comprise (s) a first container with acompound of Formula I contained therein; and (b) a second container witha second pharmaceutical formulation contained therein, wherein thesecond pharmaceutical formulation comprises a chemotherapeutic agent.The article of manufacture in this embodiment of the invention mayfurther comprise a package insert indicating that the first and secondcompounds can be used to treat patients at risk of stroke, thrombus orthrombosis disorder. Alternatively, or additionally, the article ofmanufacture may further comprise a second (or third) containercomprising a pharmaceutically-acceptable buffer, such as bacteriostaticwater for injection (BWFI), phosphate-buffered saline, Ringer's solutionand dextrose solution. It may further include other materials desirablefrom a commercial and user standpoint, including other buffers,diluents, filters, needles, and syringes.

In an embodiment, the compounds of Formula I can be used to control JAKprotein kinases, tyrosine kinases, additional serine/threonine kinases,and/or dual specificity kinases. Thus, they are useful aspharmacological standards for use in the development of new biologicaltests, assays and in the search for new pharmacological agents.

Compounds of Formula I may be assayed for the ability to modulate theactivity of JAK protein kinases, tyrosine kinases, additionalseine/threonine kinases, and/or dual specificity kinases in vitro and invivo. In vitro assays include biochemical and cell-based assay thatdetermine inhibition of the kinase activity. Alternate in vitro assaysquantify the ability of the compound of Formula I to bind to kinases andmay be measure either by radiolabelling the compound of Formula I priorto binding, isolating the compound of Formula I/kinase complex anddetermining the amount of radiolabel bound, or by running a competitionexperiment where a compound of Formula I is incubated with knownradiolabled ligands. These and other useful in vitro assays are wellknown to those of skill in the art.

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare othercompounds of Formula I, and alternative methods for preparing thecompounds of Formula I are within the scope of this invention. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, and/or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the invention.

Biological Examples

Compounds of Formula I may be assayed for the ability to modulate theactivity of Janus protein kinases, tyrosine kinases, additionalserine/threonine kinases, and/or dual specificity kinases in vitro andin vivo. In vitro assays include biochemical and cell-based assays thatdetermine inhibition of the kinase activity. Alternate in vitro assaysquantify the ability of the compound of Formula I to bind to kinases andmay be measured either by radiolabelling the compound of formula I priorto binding, isolating the compound of Formula I/kinase complex anddetermining the amount of radiolabel bound, or by running a competitionexperiment where a compound of formula I is incubated with knownradiolabeled ligands. These and other useful in vitro assays are wellknown to those of skill in the art.

Previous studies have shown that the isolated kinase domains of humanJAK1, JAK2, JAK3 or TYK2 phosphorylate peptide substrates in in vitrokinase assays (Saltzman et al., Biochem. Biophys. Res. Commun.246:627-633 (2004)). The catalytically active kinase domain of humanJAK1, JAK2, JAK3 or TYK2 was purified from extracts of SF9 insect cellsinfected with a recombinant baculovirus expression vector encoding thehuman JAK1, JAK2, JAK3 or TYK2 kinase domains (JAK1 amino acid residuesN852-D1154 according to the numbering GenBank sequence accession numberP23478, JAK2 amino acid residues D812-G1132 according to the numberingof GenBank sequence accession number NP_(—)004963.1; JAK3 amino acidresidues S783-S1124 according to the numbering of GenBank sequenceaccession number P52333, and TYK2 amino acid residues N873-C1187according to the numbering of GenBank sequence accession number P29597.)The activity of the JAK1, JAK2, JAK3 or TYK2 kinase domains can bemeasured by a number of direct and indirect methods, includingquantification of phosphorylation of peptide substrates derived from thehuman JAK3 protein (Saltzman et al., Biochem. Biophys. Res. Commun.245:627-633 (2004)). The activity of the JAK1, JAK2, JAK3 or TYK2 kinasedomains was measured in vitro by monitoring phosphorylation of JAK3derived peptides using the Caliper LabChip technology (see Examples).

EXAMPLE A JAK2 Inhibition Assay Protocol

The activity of the isolated JAK2 kinase domain was measured bymonitoring phosphorylation of a peptide derived from JAK3(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr) fluorescently labeledon the N-terminus with 5-caroxyfluorescein using the Caliper LabChiptechnology (Caliper Life Sciences, Hopkinton, Mass.). To determine theinhibition constants (Ki) of Examples 1-304, compounds were dilutedserially in DMSO and added to 50 μL kinase reactions containing 0.2 nMpurified JAk2 enzyme, 100 mM MgCl₂, 4 mM DTT at a final DMSOconcentration of 2%. Reactions were incubated at 22° C. in 384-wellpolypropylene microtiter plates for 30 minutes and then stopped byaddition of 26 μL of an EDTA containing solution (100 mM Hepes pH 7.2,0.015% Brij-35, 150 mM EDTA), resulting in a final EDTA concentration of50 nM. After termination of the kinase reaction, the proportion ofphosphorylated product was determined as a fraction of total peptidesubstrate using the Caliper LabChip 3000 according to the manufacturer'sspecifications. Ki values were then determined using the Morrison tightbinding model. Morrison, J. F. Biochem. Biophys. Acta. 185:269-295(1969); William, J. W. and Morrison, J. F., Meth. Enzymol., 63:437-467(1979).

EXAMPLE B JAK1 and TYK2 Inhibition Assay Protocol

The activity of the isolated JAK1 or TYK2 kinase domain was measured bymonitoring phosphorylation of a peptide derived from JAK3(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr) fluorescently labeledon the N-terminus with 5-carboxyfluorescein using the Caliper LabChiptechnology (Caliper Life Sciences, Hopkinton, Mass.). To determine theinhibition constants (Ki) of Examples 1-312, compounds were dilutedserially in DMSO and added to 50 μL kinase reactions containing 1.5 nMJAK1, 0.2 nM purified JAK2 or 1 nM purified TYK2 enzyme, 100 mM HepespH7.2, 0.015% Brij-35, 1.5 μM peptide substrate, 25 μM ATP, 10 mM MgCl₂,4 mM DTT at a final DMSO concentration of 2%. Reactions were incubatedat 22° C. in 384-well polypropylene microtiter plates for 30 minutes andthen stopped by addition of 26 μL of an EDTA containing solution (100 mMHepes pH 7.2, 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTAconcentration of 50 mM. After termination of the kinase reaction, theproportion of phosphorylated product was determined as a fraction oftotal peptide substrate using the Caliper LabChip 3000 according to themanufacturer's specifications. Ki values were then determined using theMorrison tight binding model. Morrison, J. F., Biochim. Biophys. Acta.185:269-295 (1969); William, J. W. and Morrison, J. F., Meth. Enzymol.,63:437-467 (1979).

EXAMPLE C JAK3 Inhibition Assay Protocol

The activity of th isolated JAK3 kinase domain was measured bymonitoring phosphorylation of a peptide derived from JAK3(Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Tyr-Val-Val-Arg) fluorescently labeled onthe N-terminus with 5-carboxyfluorescein using the Caliper LabChiptechnology (Caliper Life Sciences, Hopkinton, Mass.). To determine theinhibition constants (Ki) of Examples 1-312, compounds were dilutedserially in DMSO and added to 50 μL kinase reactions containing 5

M purified JAK3 enzyme, 100 mM Hepes pH7.2, 0.015% Brij-35, 1.5 μMpeptide substrate, 5 μM ATP, 10 mM MgCl₂, 4 mM DTT at a final DMSOconcentration of 22%. Reactions were incubated at 22° C. in 384-wellpolypropylene microtiter plates for 30 minutes and then stopped byaddition of 25 μL of an EDTA containing solution (100 mM Hepes pH 7.2,0.015% Brij-35, 150 mM EDTA), resulting in a final EDTA concentration of50 mM. After termination of the kinase reaction, the proportion ofphosphorylated product was determined as a fraction of total peptidesubstrate using the Caliper LabChip 3000 according to the manufacturer'sspecifications. Ki values were then determined using the Morrison tightbinding model. Morrison, J. F., Biochem. Biophys. Acta 185:269-296(1969); William, J. W. and Morrison, J. F., Meth. Enzymol., 63:437-467(1979).

EXAMPLE D Cell-Based Pharmacology Assays

The activates of compounds 1-312 were determined in cell-based assaysthat are designed to measure Janus kinase dependent signaling. Compoundswere serially diluted in DMSO and incubated with Set-2 cells (GermanCollection of Microorganisms and Cell Cultures (DSMZ); Braunschweig,Germany), which express the JAK2V617mutant protein, in 96-wellmicrotiter plates for 1 hr at 37° C. in RPMI medium at a final celldensity of 10⁵ cells per well and a final DMSO concentration of 0.57%.Compound-mediated effects on STAT5 phosphorylation were then measured inthe lysates of incubated cells using the Meso Scale Discovery (MSD)technology (Gaithersburg, Md.) according to the manufacturer's protocoland EC₅₀ values were determined. Alternatively, serially dilutedcompounds were added to NK92 cells (American Type Culture Collection(ATCC); Manassas, Va.) in 96-well microtiter plates in RPMI medium at afinal cell density of 10⁵ cells per well and a final DMSO concentrationof 0.57%. Human recombinant IL-12 (R&D systems; Minneapolis, Minn.) wasthen added at a final concentration of 10 ng/ml to the microtiter platescontaining the NK92 cells and compound of and the plates were incubatedfor 1 hr at 37° C. Compound-mediated effects on STAT4 phosphorylationwere then measure in the lysates of incubated cells using the Meso ScaleDiscovery (MSD) technology (Gaithersburg, Md.) according to themanufacturer's protocol and EC₅₀ values were determined.

Preparative Examples Abbreviations

-   CD₃OD Deuterated Methanol-   DCM Dichloromethane-   DIPEA Diisopropylethylamine-   DMSO Dimethylsulfoxide-   DMF Dimethylformamide-   EtOAc Ethyl Acetate-   EtOH Ethanol-   HCl Hydrochloric acid-   HM-N Isolute® HM-N is a modified form of diatomaceous earth-   IMS industrial methylated spirits-   MeOH Methanol-   POCl₃ Phosphorus oxychloride-   NaH Sodium Hydride-   Na₂SO₄ Sodium Sulfate-   NaHCO₃ Sodium bicarbonate-   NaOH Sodium hydroxide-   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)-   NEt    Triethylamine-   Pd₂dba₃ Tris-(dibenzylideneacetone)dipalladium(0)-   Si-SPE Pre-packed Isolute® silica flash chromatography cartridge-   Si-ISCO Pre-packed ISCO® silica flash chromatography cartridge-   THF Tetrahydrofuran

General Experimental Conditions

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova (400 MHz) spectrometer with a triple resonance 5 mm probe.Chemical shifts are expressed in ppm relative to tetramethylsilane. Thefollowing abbreviations have been used: br=broad signal, s=singlet,d=doublet, dd=double doublet, t=triplet, q=quartet, m=multiplet.

High Pressure Liquid Chromatography—Mass Spectrometry (LCMS) experimentsto determine retention times (R_(T)) and associated mass ions wereperformed using one of the following methods.

Method A: Experiments performed on a Waters Micromass ZQ quadrupole massspectrometer linked to a Hewlett Packard HP1100 LC system with diodearray detector. This system uses a Higgins Clipeus 5 micron C18 100×3.0mm column and a 1 ml/minute flow rate. The initial solvent system was95% water containing 0.1% formic acid (solvent A) and 5% acetonitrilecontaining 0.1% formic acid (solvent B) for the first minute followed bya gradient up to 5% solvent A and 95% solvent B over the next 14minutes. The final solvent system was held constant for a further 5minutes.

Method B: Experiments performed on a Waters Platform LC quadrupole massspectrometer linked to a Hewlett Packard HP1100 LC system with diodearray detector and 100 position autosampler using a Phenomenex LunaC18(2) 30×4.6 mm column and a 2 ml/minute flow rate. The solvent systemwas 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for the first 0.50minutes followed by a gradient up to 5% solvent A and 95% solvent B overthe next 4 minutes. The final solvent system was held constant for afurther 0.50 minutes.

Microwave experiments were carried out using a Biotage Initiator 60™ orCEM Explorer®. Temperatures from 40-250° C. can be achieved, andpressures of up to 30 bar can be reached.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, LancasterTCI or Maybridge, and were used without further purification unlessotherwise indicated.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was conducted on a Combiflash system(Manufacturer: Teledyne Isco) having a silica gel column. ¹H NMR spectrawere recorded on a Varian instrument operating at 400 MHz. ¹H NMRspectra were obtained as CDCl₃, d₆-DMSO or d₄ MeOH solutions (reportedin ppm), using chloroform as the reference standard (7.25 ppm). Whenpeak multiplicities are reported, the following abbreviations are use: s(singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd(double of doublets), dt (doublet of triplets). Coupling constants, whengiven, use reported in Hertz (Hz).

Example 1

N-Piperidin-4-yl-4-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino]-benzamide

Ethyl [(3-bromopyridin-2-yl) carbamothiol]carbamate

To a solution of 2-amino-3-bromopyridine (50.0 g, 289 mmol, 1 equiv) indichloromethane (500 mL) was added dropwise ethoxycarbonylisothiocyanate (39.0 g, 297 mmol, 1.03 equiv) at room temperature. After2 h, dichloromethane was removed in vacuo to provide crude ethyl[(3-bromopyridin-2-yl)carbamothioyl]carbamate (88 g).

8-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine

To a solution of hydroxylamine hydrochloride (0.10 kg, 1.4 mol, 5.0equiv) and N,N-diisopropylethylamine (112 g, 0.867 mol, 3.00 eq) in 1:1methanol/ethanol (1.5 L) was added ethyl[(3-bromopyridin-2-yl)carbamothioyl]carbamate (88 g, 0.29 mmol, 1 equiv)in one portion at room temperature. After 2 h, the reaction mixture waswarmed to 60° C. for overnight. The reaction mixture was concentrated invacuo, and water was added to the resulting residue. The solids werefiltered and rinsed sequentially with 4:1 methanol/diethyl ether anddiethyl ether to provide product as an off-white solid (25 g, 40%). LCMS(ESI) m/z: 212.8; ¹NMR (400 MHz, DMSO-d₆) δ: 8.55 (m 1 H), 7.70 (m, 1H), 6.75 (m, 1 H), 6.20 (br s, 2 H).

Di-tert-butyl(8-bromo[1,2,4]triazolo[1,5-α]pyridin-2-yl)imidodicarbonate

A solution of 8-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (10.6 g,49.7 mmol, 1 equiv), di-tert-butyl dicarbonate (43.6 g, 0.200 mol, 4.01eqiv), and 4-dimethylaminopyridine (0.61 g, 5.0 mmol, 0.10 equiv) inpyridine (200 mL) was heated at 50° C. overnight. The reaction mixturewas concentrated in vacuo. The resulting residue was partitioned betweenwater and diethyl ether. The organic layer was separated and washed withwater (3×). Filtration of the organic through a plug of silica gel (4:1petroleum ether/ethyl acetate) afforded crude product. (14.8 g, 72%). ¹HNMR (400 MHz), DMSO-d₆) δ: 9.0 (m, 1 H), 8.1 (m, 1 H), 7.2 (m, 1 H), 1.4(s, 18 H).

8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

To a solution of di-tert-butyl(8-bromo[1,2,4]triazolo[1,5-α]pyridin-2-yl)imidodicarbonate (3.3 g, 8.0mmol, 1 equiv), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (0.584 g, 0.798 mmol, 0.10 equiv), cesium carbonate (3.1 g, 9.5mmol, 1.2 equiv), and 3-trifluoromethylphenyl boronic acid (1.8 g, 9.5mmol, 1.2 equiv) in 10:1 1,2-dimethoxyethane/water (50 mL) was heated at120° C. overnight. The reaction mixture was concentrated in vacuo, andthe resulting residue was partitioned between ethyl acetate and water.The collected organic was dried over anhydrous sodium sulfate, filtered,and concentrated. Purification by the flash column chromatography (4:1petroleum ether/ethyl acetate) afforded di-tert-butyl(8-(3-trifluoromethylphenyl[1,2,4]triazolo[1,5-α]pyridin-2-yl)imido-dicarbonate(3.17 g, 83%).

Di-tert-butyl(8-(3-trifluoromethylphenyl[1,2,4]triazolo[1,5-α]pyridin-2-yl)imido-dicarbonate(3.15 g, 6.58 mmol, 1 equiv) was dissolved in a solution of hydrogenchloride in dioxane (50 mL). The reaction mixture was maintained at roomtemperature overnight. Dioxane was removed in vacuo, and the resultingresidue was dissolve in dichloromethane (100 mL). The organic was washedsequentially with saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution. The organic was dried overanhydrous sodium sulfate, filtered, and concentrated to yield product(1.41 g, 77%). LCMC (ESI) m/z: 279.1.

Methyl4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoate

A suspension of8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (1.0g, 3.6 mmol, 1 equiv), methyl-4-iodobenzoate (0.95 g, 3.6 mmol, 1.0equiv), palladium (II) acetate (0.080 g, 0.36 mmol, 0.10 equiv), cesiumcarbonate (2.34 g, 7.18 mmol, 2.0 equiv), and Xantphos (0.10 g, 0.17mmol, 0.047 equiv) in 1,4-dioxane (20 mL) was heated to 80° C. After 16h, the reaction mixture was concentrated in vacuo, and the resultingresidue was diluted with methanol and water. The solid was collected byfiltration and rinsed sequentially with water, isopropanol, and hexanesto afford crude methyl4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoate(1.07 g, 72%). LCMS (ESI) m/z: 413.0; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.29(s, 1 H), 8.88 (m, 1 H), 8.63 (s, 1 H), 8.40 (m, 1 H), 8.02 (m, 1 H),7.78-7.90 (m, 6 H), 7.2 (m, 1 H), 3.80 (s, 3 H).

4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoicacid

A solution of methyl4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoate(1.03 g, 2.50 mmol, 1 equiv) in 2M aqueous sodium hydroxide (10 mL) and1,4-dioxane (5 mL) was heated at 80-90° C. After 3 h, the solution wascooled to 0° C. and neutralized by the addition of 6M HCl until pH=4-5.The resulting solid was collected by filtration and rinsed sequentiallywith water, isopropanol, and hexanes to afford crude4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoicacid (1.0 g, HPLC purity: 89%). LCMS (ESI) m/z: 398.9; ¹H NMR (400 MHz,DMSO-d₆) δ: 12.45 (br s, 1 H), 10.22 (s, 1 H), 8.89 (d, J=6.8 Hz, 1 H),8.65 (s, 1 H), 8.42 (d, J=6.9 Hz, 1 H), 8.03 (m, 1 H), 7.77-7.84 (m, 6H), 7.21 (d, J=7.0 Hz, 1 H).

N-Piperidin-4-yl-4-[8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino]benzamide

To a solution of4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoicacid (1.0 g, 2.5 mmol, 1 equiv),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (1.14 g, 3.00 mmol, 1.2 equiv),N,N-diisopropylethylamine (484 mg, 3.74 mmol, 1.5 equiv) in 2:1tetrahydrofuran/dichloromethane (50 mL) was added tert-butyl4-amino-1-piperidinecarboxylate (0.60 g, 3.0 mmol, 1.2 equiv) at roomtemperature. After 16 h, the reaction mixture was filtered, and thefiltrate was concentrate. The resulting residue was was dissolved in 1:1trifluoroacetic acid/tetrahydrofuran (50 mL) at room temperature. After2 h, the reaction mixture was concentrated in vacuo. Purification bypreparative HPLC provided product (508 mg, 42%). LCMS (ESI) m/z: 481.0;¹H NMR (400 MHz, DMSO-d₆) δ: 10.06 (s, 1 H), 8.85 (d, J=7.6 Hz, 1 H),8.60 (s, 1 H), 8.38 (d, J=8.8 Hz, 1 H), 7.98 (d, J=8.8 Hz, 1 H), 7.84(br s, 2 H), 7.72-7.79 (m, 3 H), 7.32 (d, J=7.6 Hz, 2 H), 7.15 (m, 1 H),4.02 (m, 1 H), 3.27-3.32 (m, 2 H), 2.95-3.05 (m, 2 H), 1.87-1.94 (m, 2H), 1.41-1.48 (m, 2 H).

Example 2

[8-(3-Methoxy-phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-yl]-(2-methyl-pyridin-4-yl)-amine

8-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

Made by following the procedure described for the preparation of8-(3-trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine butsubstituting 3-methoxyphenyl boronic acid and making non-criticalvariations.

[8-(3-Methoxy-phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-yl]-(2-methyl-pyridin-4-yl)-amine

A suspension of8-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (0.150 g,0.625 mmol, 1 equiv), 4bromo-2-methylpyridine (0.160 g, 0.935 mmol, 1.5equiv), tris(dibenzylideneacetone)dipalladium (O) (27.5 mg, 0.03 mmol,0.05 equiv), sodium tert-butoxide (0.90 g, 0.94 mmol, 1.5 equiv), and2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl (38.9 mg, 0.625 mmol,0.1 equiv) in toluene (2mL) was purged with nitrogen for 15 min. Thereaction mixture was heated at 110° C. by microwave for 10 min. Thereaction mixture was diluted with ethyl acetate (50 mL) and filteredthrough celite. The filtrate was then washed with brine (3×20 mL), driedover anhydrous sodium sulfate, filtered, and concentrated. Purificationby preparative HPLC afforded8-(3-methoxyphenyl)-N-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine(80 mg, 39%). LCMS (ESI) m/z: 332.1; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.45(br s, 1 H), 8.81 (dd, J=6.4, 0.8 Hz, 1 H), 8.23 (d, J=6.0 Hz, 1 H),7.88 (dd, J=6.8, 0.8 Hz, 1 H), 7.74 (s, 1 H), 7.64 (d, J=8.0 Hz, 1 H),7.57 (s, 1 H), 7.54 (dd, J=6.0, 2.0 Hz, 1 H), 7.41 (t, J=8.0 Hz, 1 H),7.15 (t, J=6.8 Hz, 1 H), 7.00 (dd, J=8.0, 2.4 Hz, 1 H), 3.83 (s, 3 H),2.42 (s, 3 H).

Examples 3-126 shown in Table 1 were prepared according to theabove-described methods.

TABLE 1 LCMS (ESI) Ex # Structure Name m/z  3

(3,5-Difluoro-phenyl)-[8-(3- methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl]-amine 353.1  4

[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl]-pyridin-4-yl-amine 318.0  5

(3-Fluoro-phenyl)-[8-(3- methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl]-amine 335.0  6

[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2- yl]-phenyl-amine317.1  7

(3,5-Difluoro-phenyl)-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl]-amine 406.0  8

(2-Methyl-pyridin-4-yl)-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl]-amine 385.9  9

(3-Fluoro-phenyl)-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl]-amine 388.9  10

(4-Fluoro-phenyl)-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- yl]-amine 388.0  11

Phenyl-[8-(3-trifluoromethoxy- phenyl)-[1,2,4]triazolo[-1,5-a]pyridin-2-yl]-amine 370.9  12

[8-(2-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2- yl]-phenyl-amine304.9  13

(3-Fluoro-phenyl)-(8-m-tolyl- [1,2,4]triazolo[1,5-a]pyridin-2- yl)-amine318.9  14

(2-Methyl-pyridin-4-yl)-(8-m- tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine 318.9  15

(4-Fluoro-phenyl)-(8-m-tolyl- [1,2,4]triazolo[1,5-a]pyridin-2- yl)-amine318.9  16

N,N-Dimethyl-4-(8-p-tolyl [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 371.9  17

4-[8-(4-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-cyclohexyl- benzamide 446.1  18

N-(2-Piperazin-1-yl-ethyl)-4-[8- (3-trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 526.1  19

N-(2-Morpholin-4-yl-ethyl)-4-(8- p-tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 457.0  20

N-Methyl-4-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 427.9  21

4-[8-(3-Trifluoromethoxy- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzamide 416.0  22

4-(8-m-Tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzamide 344.1 23

N-(2-Morpholin-4-yl-ethyl)-4-(8- m-tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 457.2  24

4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(1-methyl-piperidin- 4-yl)-benzamide 457.2  25

4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-piperidin-4-yl- benzamide 443.1  26

4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-piperidin-4-ylmethyl- benzamide 457.2  27

4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(2-morpholin-4-yl- ethyl)-benzamide 473.1  28

N-Cyclohexyl-4-[8-(4-methoxy- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzamide 442.1  29

N-(2-Amino-2-methyl-propyl)-4- [8-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 431.1  30

4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(3-morpholin-4-yl- propyl)-benzamide 487.1  31

4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(1-methyl-piperidin- 4-ylmethyl)-benzamide 471.2  32

4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N,N-dimethyl- benzamide 486.1  33

4-[8-(4-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(1-methyl-piperidin- 4-yl)-benzamide 461.1  34

4-[8-(4-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(2-morpholin-4-yl- ethyl)-benzamide 461.1  35

N-Cyclohexyl-4-[8-(4-fluoro- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzamide 430.1  36

4-[8-(4-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(3-morpholin-4-yl- propyl)-benzamide 475.1  37

4-[8-(4-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N,N-dimethyl- benzamide 376.1  38

4-[8-(4-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoic acid 361.1  39

N-(2-Amino-2-methyl-propyl)-4- [8-(4-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 419.1  40

4-[8-(4-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoic acid 346.9  41

4-(8-p-Tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzoic acid344.9  42

4-[8-(4-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoic acid 364.8  43

4-[8-(4-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(1-methyl-piperidin- 4-yl)-benzamide 461.2  44

4-[8-(4-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(2-morpholin-4-yl- ethyl)-benzamide 477.2  45

4-[8-(4-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N,N-dimethyl- benzamide 392.1  46

(2-[4-[8-3-Trifluoromethoxy- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]- benzoylamino]-ethyl)-carbamic acid tert-butylester 557.0  47

(3-(4-[8-(3-Trifluoromethyl- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)- benzoylamino)-ethyl]-carbamic acid tert-butylester 541.1  48

{2-[4-(8-m-Tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzoylamino]-ethyl)- carbamic acid tert-butyl ester 457.1  49

N-(2-Dimethylamino-ethyl)-4-[8- p-tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 415.0  50

N-(1-Methyl-piperidin-4-yl)-4-(8- p-tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 441.1  51

N-Piperidin-4-yl-4-(8-p-tolyl [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 427.0  52

(2-[4-(8-p-Tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzoylamino]-ethyl)- carbamic acid tert-butyl ester 487.1  53

N-Cyclohexyl-4-(8-p-tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 426.1  54

N-Cyclohexyl-4-[8-(3-methoxy- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzamide 442.0  55

4-[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(1-methyl-piperidin- 4-yl)-benzamide 457.1  56

4-[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-piperidin-4-ylmethyl- benzamide 457.1  57

4-[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(2-morpholin-4-yl- ethyl)-benzamide 473.1  58

N-(2-Amino-2-methyl-propyl)-4- [8-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 431.1  59

N-(2-Dimethylamino-ethyl)-4-[8- (3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 431.1  60

N-(2-Amino-ethyl)-4-[8-(3- methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 403.0  61

4-[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-piperidin-4-yl- benzamide 443.0  62

4-[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N,N-dimethyl- benzamide 388.0  63

4-[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-methyl-benzamide 374.0  64

N-Cyclohexyl-4-[8-(3-fluoro- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzamide 430.1  65

4-[8-(3-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(3-morpholin-4-yl- propyl)-benzamide 475.1  66

4-[8-(3-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(1-methyl-piperidin- 4-yl)-benzamide 445.2  67

4-[8-(3-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-piperidin-4-ylmethyl- benzamide 445.0  68

4-[8-(3-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(2-morpholin-4-yl- ethyl)-benzamide 461.2  69

N-(2-Amino-2-methyl-propyl)-4- [8-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 419.2  70

N-(2-Dimethylamino-ethyl)-4-[8- (3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 419.2  71

N-(2-Amino-ethyl)-4-[8-(3- fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 391.3  72

4-[8-(3-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-piperidin-4-yl- benzamide 431.0  73

4-[8-(3-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-methyl-benzamide 362.1  74

N-(3-Morpholin-4-yl-propyl)-4- [8-(3-trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 541.1  75

N-[2-Amino-2-methyl-propyl)-4- [8-(3-trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 485.0  76

N-Cyclohexyl-4-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 496.0  77

N-Piperidin-4-yl-4-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino)-benzamide 496.9  78

N-Piperidin-4-ylmethyl-4-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 511.0  79

N-(1-Methyl-piperidin-4-yl)-4-[8- (3-trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 511.0  80

N-(2-Morpholin-4-yl-ethyl)-4-[8- (3-trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 527.0  81

N,N-Dimethyl-4-[8-(3- trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 441.9  82

N-(2-Dimethylamino-ethyl)-4-[8- (m-tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 415.2  83

N-(3-Morpholin-4-yl-propyl)-4- (8-m-tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 471.3  84

N-(2-Amino-2-methyl-propyl)-4- (8-m-tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 416.3  85

N-Cyclohexyl-4-(8-m-tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 425.3  86

N-Piperidin-4-ylmethyl-4-(8-m- tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 441.2  87

N-(1-Methyl-piperidin-4-yl)-4-(8- m-tolyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 441.2  88

N,N-Dimethyl-4-(8-m-tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 372.1  89

N-Methyl-4-(8-m-tolyl- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-benzamide 358.1  90

N-(2-Dimethylamino-ethyl)-4-[8- (3-trifluoromethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 485.0  91

4-(8-m-Tolyl-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)-benzoic acid345.1  92

4-[8-(3-Trifluoromethoxy- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoic acid 415.1  93

4-[8-(3-Trifluoromethyl-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzamide 396.1  94

N-(2-Dimethylamino-ethyl)-4-[8- (3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 469.0  95

N-(2-Amino-2-methyl-propyl)-4- [8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 469.0  96

N-[3-(4-Methyl-piperazin-1-yl)- propyl]-4-[8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino]-benzamide 536.1  97

N-(1-Methyl-piperidin-4- ylmethyl)-4-[8-(3- trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 509.1  98

N-(2-Piperazin-1-yl-ethyl)-4-[8- (3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 510.2  99

N,N-Dimethyl-4-[8-(3- trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 426.1 100

N-Piperidin-4-ylmethyl-4-[8-(3- trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 495.0 101

N-Methyl-4-[8-(3- trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 412.1 102

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(1-methyl-piperidin- 4-ylmethyl)-benzamide 475.2 103

N-(2-Amino-2-methyl-propyl)-4- [8-(3-chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-3- ylamino]-benzamide 435.2 104

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(2-dimethylamino- ethyl)-benzamide 435.2 105

N-(2-Amino-ethyl)-4-[8-(3- chloro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 407.1 106

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-methyl-benzamide 376.1 107

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzamide 363.8 108

4-[8-(3-Fluoro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzamide 349.1 109

4-[8-(3-Methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoic acid 360.9 110

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(2-morpholin-4-yl- ethyl)-benzamide 477.0 111

4-[8-(3-Chlorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(3-morpholin-4-yl- propyl)-benzamide 491.1 112

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-piperidin-4-ylmethyl- benzamide 461.0 113

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-[3-(4-methyl- piperazin-1-yl)-propyl]- benzamide 504.1 114

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-[2-(4-methyl- piperazin-1-yl)-ethyl]- benzamide 490.0 115

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-piperidin-4-yl- benzamide 447.2 116

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(2-piperazin-1-yl- ethyl)-benzamide 476.1 117

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-(1-methyl-piperidin- 4-yl)-benzamide 461.2 118

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N-cyclohexyl- benzamide 446.0 119

N-Cyclohexyl-4-[8-(3- trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 480.1 120

N-(1-Methyl-piperidin-4-yl)-4-[8- (3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 495.1 121

N-(2-Morpholin-4-yl-ethyl)-4-[8- (3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 511.1 122

N-(3-Morpholin-4-yl-propyl)-4- [8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2- ylamino]-benzamide 525.1 123

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoic acid 365.0 124

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-N,N-dimethyl- benzamide 392.1 125

4-[8-(3-Chloro-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoic acid methyl ester 379.0 126

4-[8-(3-Trifluoromethoxy- phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-benzoic acid methyl ester 429.0

Example 127

4-(8-(1-cyclopentyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoicacid

methyl 4-(8-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoate

A suspension of 8-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-amine (2.8 g,13.2 mmol, 1 equiv), methyl 4-iosobenzoate (3.4 g, 13 mmol, 1 equiv),cesium carbonate (8.4 g, 26 mmol, 2.0 equiv),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (763 mg, 1.32 mmol, 0.10equiv), and palladium (II) acetate (300 mg, 1.32 mmol, 0.10 equiv) indioxane (100 mL) was heated at 80° C. for 1 h. The reaction mixture wascooled to room temperature and diluted with dichloromethane (100 mL).The resulting solids were filtered and sequentially rinsed with water(3×50 mL) and methanol (2×20 mL). The solids were dried in vacuo toafford methyl4-(8-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoate (3.1 g). ¹HNMR (400 MHz, DMSO-d₆) δ: 10.42 (s, 1 H), 8.87 (m, 1 H), 7.93 (m, 1 H),7.92 (d, J=8.8 Hz, 2 H), 7.77 (d, J=8.8 Hz, 2 H), 7.00 (dd, J=7.4, 6.9Hz, 1 H), 3.81 (s, 1 H).

methyl4-(8-(1-cyclopentyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoate

A suspension of methyl4-(8-bromo-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoate (0.800 g,2.30 mmol, 1 equiv),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (894 mg,4.60 mmol, 2.00 equiv),1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (376 mg,0.461 mmol, 0.200 equiv), and cesium carbonate (1.50 g, 4.61 mmol, 2.00equiv) in 5:1 1,2-dimethoxyethane/water (6 mL) was evacuated andback-filled with nitrogen (3×). The reaction mixture was heated at 140°C. for 30 min in the microwave. LCMS of the reaction mixture showed −60%conversion, and additional bis(diphenylphosphino)ferrocenepalladium(II)chloride (95 mg, 0.12 mmol, 0.05 equiv) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (225 mg,1.16 mmol, 0.500 equiv) were added. The reaction mixture was then heatedat 140° C. for 30 min in the microwave. The solids were collected byfiltration and purified by flash column chromatography (10% methanol, 1%ammonium hydroxide in dichloromethane) to afford a gray solid (620 mg,80% yield). LCMS (ESI) m/z: 335.0.

methyl4-(8-(1-cyclopentyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoate

A suspension of methyl4-(8-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoate(43 g, 0.13 mmol, 1 equiv), cyclopentyl bromide (41 μL, 0.38 mmol, 3.0equiv), and cesium carbonate (126 mg, 0.383 mmol, 3.0 equiv) inN,N-dimethylformamide (1 mL) was heated at 100° C. After 2 h, thereaction mixture was diluted with ethyl acetate, and the resultingsolution was washed with saturated aqueous sodium chloride solution. Thecollected organic was concentrated. Purification of the resultingresidue by flash column chromatography (20% ethyl acetate indichloromethane) afforded a white solid (23.5 mg, 45% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 10.18 (s, 1 H), 8.74-8.55 (m, 2 H), 8.32 (s, 1 H),7.91 (dd, J=13.9, 8.1 Hz, 3 H), 7.85 (d, J=8.9 Hz, 2 H), 7.85 (d, J=8.9Hz, 2 H), 7.10 (t, J=7.0 Hz, 1 H), 4.81 (s, 1 H), 3.82 (s, 3 H),2.25-2.11 (m, 2), 2.11-1.93 (m, 2 H), 1.85 (d, J=3.5 Hz, 2 H), 1.77-1.63(m, 2 H).

4-(8-(1-Cyclopentyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)benzoicacid

Made by following the procedure described for the preparation of4-(8-(3-trifluoromethyl)phenyl-[1,2,4]triazolo[1,5-α]pyridine-2-ylamino)benzoicacid and making non-critical variations. ¹H NMR (400 MHz, DMSO-d₆) δ12.43 (s, 1 H), 10.12 (s, 1 H), 8.74-8.60 (m, 2 H), 8.32 (s, 1 H), 7.90(t, J=6.8 Hz, 3 H), 7.83 (d, J=8.8 Hz, 2 H), 7.09 (s, 1 H), 4.81 (d,J=7.0 Hz, 1 H), 2.16 (m, 2 H), 2.00 (m, 2 H), 1.94-1.79 (m, 2 H), 1.72(dd, J=14.6, 8.1 Hz, 2 H).

Example 128

(R)-1-(4-(8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)-1H-pyrazol-1-yl)propan-2-ol

-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

Made by following the procedure described for the preparation of8-(3-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine with4-methoxyphenyl boronic acid and making non-critical variations.

2-iodo-8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridine

A solution of potassium iodide (5.4 g, 32 mmol, 3.9 equiv) and sodiumnitrite (1.73 g, 25.1 mmol, 3.00 equiv) in water (10 mL) was added over5 min to a solution of8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine (2.01 g, 8.36mmol, 1 equiv) and p-toluenesulfonic acid (7.3 g, 38 mmol, 4.6 equiv) inacetonitrile at 24° C. After 19 h, the reaction was diluted with ethylacetate (250 mL), and the resulting solution was washed sequentiallywith water (2×120 mL) and saturated aqueous sodium chloride solution(120 mL). The collected organic was dried over magnesium sulfate,filtered, and concentrated in vacuo. Purification by flash columnchromatography (20→30% ethyl acetate in heptane) provided product as alight yellow solid (1.93 g, 65% yield). ¹H NMR (400 MHz, DMSO-d₆) δ:8.46 (dd, J=6.8, 1.0 Hz, 1 H), 7.96 (m, 2 H), 7.59 (dd, J=7.4, 1.1 Hz, 1H), 7.01-7.06 (m, 3 H), 3.86 (s, 3 H).

Preparation of (R)-1-(4-amino-1H-pyrazol-1-yl)propan-2-ol

To a solution of 4-nitropyrazole (44.7 mg, 0.395 mmol, 1 equiv) in(R)-propylene oxide (1 mL) was added cesium carbonate (78 mg, 0.24 mmol,0.61 equiv) at 24° C. After 64 h, the reaction mixture was partitionedbetween ethyl acetate (3 mL) and half-saturated aqueous sodium chloridesolution (3 mL). The organic was separated, and the remaining aqueousphase was extracted with ethyl acetate (2×3 mL). The collected organicwas dried over anhydrous sodium sulfate, filtered, and concentrated. Theresulting residue was dissolved in methanol (4 mL) and circulatedthrough a H-Cube® continuous-flow hydrogenation reactor (ThalesNano)fitted with a palladium on carbon catalyst cartridge at 30° C. Theresulting solution was concentrated in vacuo to provide product as apink oil, which was used without further purification. ¹H NMR (500 MHz,CDCl₃), δ: 7.17 (s, 1 H), 7.01 (s, 1 H), 4.13 (m, 1 H), 4.00 (dd,J=13.8, 2.7 Hz, 1 H), 3.84 (dd, J=13.8, 7.9 Hz, 1 H), 3.47 (s, 1 H),3.15 (br s, 2 H), 1.18 (d, J=6.3 Hz, 3 H).

(R)-1-(4-(8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)-1H-pyrazol-1-yl)propan-2-ol

A suspension of2-iodo-8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridine (53.6 mg,0.153 mmol, 1 equiv), (R)-1-(4-amino-1H-pyrazol-1-yl)propan-2-ol (27 mg,0.19 mmol, 1.2 equiv), sodium tert-butoxide (43.1 mg, 0.448 mmol, 2.94equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.2 mg, 0.0263mmol, 0.172 equiv) and tris(dibenylidenacetone)dipalladium (O) (10.5 mg,0.0115 mmol, 0.0751 equiv) in dioxane (2 mL) was heated at 170° C. inthe microwave for 15 min. The reaction mixture was partitioned betweensaturated aqueous sodium chloride solution (5 mL) and ethyl acetate (5mL). The organic was separated, and the aqueous layer was extracted withethyl acetate (2×5 mL). The collected organic was dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. Purification byflash column chromatography (5% methanol in dichloromethane) affordedproduct as a white solid (42.4 mg, 73% yield). ¹H NMR (400 MHz,DMSO-d₆), δ: 9.32 (s, 1 H, NH), 8.64 (dd, J=6.6, 0.9 Hz, 1 H), 8.13 (dd,J=8.8 Hz, 2 H), 7.81 (s, 1 H), 7.74 (dd, J=7.5, 0.9 Hz, 1 H), 7.47 (s, 1H), 7.08 (d, J=8.9 Hz, 2 H), 7.03 (t, J=7.0 Hz, 1 H), 4.92 (d, J=4.7 Hz,1 H, OH), 3.96 (m, 3 H), 3.83 (s, 3 H), 1.04 (d, J=5.8 Hz, 3 ).

Example 129

8-(4-Methoxyphenyl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole

Procedure adapted from Zabierek, A. A.; Konrad, K. M.; Haidle, A. M.Tetrahedron Lett. 2008, 49, 2996.

To a solution of 4-nitro-1H-pyrazole (0.40 mg, 3.5 mmol, 1 equiv),4-hydroxy-tetrahydropyran (0.36 g, 3.6 mmol, 1.0 equiv) andtriphenylphosphine (1.1 g, 4.2 mmol, 1.3 equiv) in tetrahydrofuran (10mL) at 20° C. was added dibenzylazodicarboxylate (1.1 g, 4.6 mmol, 1.3equiv) in tetrahydrofuran (2 mL) over 5 min. After 3 h the reactionmixture was concentrated in vacuo, and the resulting residue waspurified by flash column chromatography (40% ethyl acetate in hexanes)to afford product as white solid (568 mg, 81% yield). ¹H NMR (400 MHz,CD₃OD) δ 8.64 (s, 1H), 8.13 (s, 1H), 4.49 (s, 1H), 4.15-3.94 (m, 2H),3.72-3.45 (m, 2H), 2.24-1.95 (m, 4H).

1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine

A solution of 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (568 mg,2.88 mmol, 1 equiv) in methanol was circulated through a H-Cube®Continuous-flow hydrogenation reactor (ThalesNano) fitted with apalladium on carbon catalyst cartridge at 50° C. The collected solutionwas concentrated in vacuo to afford product as pink solid (458 mg, 95%yield). LCMS (ESI) m/z: 168.0.

8-(4-Methoxyphenyl)-N-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-α]pyridin-2-amine

Made by following the procedure described for the preparation of(R)-1-(4-(8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-α]pyridin-2-ylamino)-1H-pyrazol-1-yl)propan-2-olwith 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine and makingnon-critical variations. ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.64(dd, J=6.6, 0.9 Hz, 1 H), 8.14 (d, J=8.9 Hz, 2 H), 7.87 (s, 1 H), 7.73(m, 1 H), 7.50 (s, 1 H), 7.08 (d, J=8.9 Hz, 3 H), 4.35 (m, 1 H), 3.98(dd, J=13.4, 10.9 Hz, 2 H), 3.83 (s, 3 H), 3.47 (m, 2 H), 1.93 (m, 4 H).

Examples 130-312 shown in Table 2 were prepared according to theabove-described methods.

TABLE 2 LCMS Ex Structure Name (ESI) m/z 130

methyl 4-(8-(1-cyclopentyl- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 403.2 131

N,N-dimethyl-4-(8-(3- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzamide 436.2 132

azetidin-1-yl(4-(6-(3- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2- ylamino)phenyl)methanone 448.1 133

(3-methoxyazetidin-1-yl)(4- (8-(3- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2- ylamino)phenyl)methanone 478.2 134

2-(4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)ethanol 351.2 135

5-(6-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)picolinic acid 362.1 136

(3-hydroxyazetidin-1-yl)(4- (8-(3- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2- ylamino)phenyl)methanone 464.0 137

(R)-(3-hydroxypyrrolidin-1- yl)(4-(8-(3- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2- ylamino)phenyl)methanone 476.2 138

(R)-(3-hydroxypiperidin-1- yl)(4-(8-(3- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2- ylamino)phenyl)methanone 492.1 139

(S)-(3-hydroxypyrrolidin-1- yl)(4-(8-(3- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2- ylamino)phenyl)methanone 478.2 140

(S)-(3-hydroxypiperidin-1- yl)(4-(8-(3- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2- ylamino)phenyl)methanone 492.1 141

5-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-N,N-dimethylpicolinamide 289.2 142

(3-aminoazetidin-1-yl)(4-(8- (3-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2- ylamino)phenyl)methanone 463.1 143

(R)-2-(4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)propan-1-ol 365.2 144

(S)-2-(4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)propan-1-ol 365.1 145

2-fluoro-4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 379.0 146

2,6-difluoro-4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 397.1 147

8-(4-isocyanophenyl)-N-(1- methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 316.2 148

N-(1-methyl-1H-pyrazol-4- yl)-5-(4- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 369.1 149

4-(2-(1-ethyl-1H-pyrazol-4- ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile 330.1 150

N-(1-ethyl-1H-pyrazol-4-yl)- 8-(4- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 383.1 151

(R)-1-(4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)propan-2-ol 415.2 152

(R)-4-(2-(1-(2- hydroxypropyl)-1H-pyrazol- 4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 360.1 153

(R)-4-(2-(1-(1- hydroxypropan-2-yl)-1H- pyrazol-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 360.1 154

(S)-4-(2-(1-(1- hydroxypropan-2-yl)-1H- pyrazol-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 360.2 155

4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-2-methylbenzoic acid 375.1 156

(S)-1-(4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)propan-2-ol 385.1 157

(R)-2-(4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)propan-1-ol 413.1 158

(S)-4-(2-(1-(2- hydroxypropyl)-1H-pyrazol- 4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 360.1 159

(S)-1-(4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)propan-2-ol 413.2 160

(S)-2-(4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)propan-1-ol 413.1 161

2-chloro-4-(8-(4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 395.1 162

2-chloro-4-(8-(4- cyanophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 390.0 163

N,N-dimethyl-8-(8-(4- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzamide 430.4 164

(4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)(morpholino) methanone 476.1 165

8-(4-methoxyphenyl)-N-(1- (tetrahydrofuran-3-yl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 377.2 166

8-(4- (methylsulfonyl)phenyl)-N- (1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 425.1 167

8-(4-isocyanophenyl)-N-(1- (tetrahydrofuran-3-yl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 372.1 168

(4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)(pyrrolidin- 1-yl)methanone 462.1 169

4-(8-(4-cyanophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-N,N-dimethylbenzamide 383.2 170

4-(8-(4-cyanophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoicacid 366.3 171

2-(4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1- yl)acetic acid 365.1 172

8-(4-methoxyphenyl)-N-(1- (1-methylpyrrolidin-3-yl)- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 390.2 173

4-(8-(4-cyanophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-2-(trifluoromethyl)benzoic acid 424.0 174

4-(2-(1-(1-methylpyrrolidin- 3-yl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 385.2 175

N-(1-(1-methylpyrrolidin-3- yl)-1H-pyrazol-4-yl)-8-(4-(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 438.1176

4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-2-(trifluoromethyl)benzoic acid 429.1 177

(S)-4-(2-(4-(2- hydroxypiperidine-1- carbonyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 439.0 178

(R)-4-(2-(4-(3- hydroxypiperidine-1- carbonyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 439.0 179

8-(4-methoxyphenyl)-N-(1- ((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine391.1 180

8-(4- (methylsulfonyl)phenyl)-N- (1-(tetrahydrofuran-3-yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine439.1 181

4-(2-(1-((tetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 386.2 182

8-(4-methoxyphenyl)-N-(1- ((1-methylpyrrolidin-3-yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine404.2 183

N-(1-((1-methylpyrrolidin-3- yl)methyl)-1H-pyrazol-4-yl)- 8-(4-(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 452.1184

4-(2-(1-((1-methylpyrrolidin- 3-yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazol[1,5- a]pyridin-8-yl)benzonitrile 389.2 185

(S)-4-(2-(4-(3- hydroxypyrrolidine-1- carbonyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 424.9 186

(R)-4-(2-(4-(3- hydroxypyrrolidine-1- carbonyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 425.0 187

3-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoicacid 361.1 188

8-(4-methoxyphenyl)-N-(1- ((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine405.2 189

8-(4- (methylsulfonyl)phenyl)-N- (1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine453.1 190

4-(2-(1-((tetrahydro-2H- pyran-4-yl)methyl)-1H- pyrazol-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 400.2 191

4-(2-(1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 386.2 192

8-(4- (methylsulfonyl)phenyl)-N- (1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 439.1 193

4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-2,6-dimethylbenzoic acid 389.1 194

8-(4-methoxyphenyl)-N-(1- ((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine416.2 195

N-(1-((1-methylpiperidin-4- yl)methyl)-1H-pyrazol-4-yl)- 8-(4-(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 456.2196

4-(2-(1-((1-methylpiperidin- 4-yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 413.2 197

8-(4-methoxyphenyl)-N-(1- (1-methylpiperidin-4-yl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 404.2 198

N-(1-(1-methylpiperidin-4- yl)-1H-pyrazol-4-yl)-8-(4-(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine 452.1199

4-(2-(1-(1-methylpiperidin- 4-yl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 399.2 200

N-ethyl-N-methyl-4-(8-(4- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzamide 450.1 201

4-(8-(3-isopropylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 373.1 202

3-(8-(3-isopropylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 373.1 203

(R)-4-(2-(1-((tetrahydro-2H- pyran-2-yl)methyl)-1H- pyrazol-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 400.0 204

(R)-4-(2-(1-((1- methylpiperidin-2- yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 413.2 205

(S)-4-(2-(1-((tetrahydro-2H- pyran-2-yl)methyl)-1H- pyrazol-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl]benzonitrile 400.0 206

(S)-4-(2-(1-((1- methylpiperidin-2- yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 413.2 207

4-(8-(1-isobutyl-1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 377.1 208

3-(8-(1-isobutyl-1H-pyrazol- 4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 377.2 209

N-(4-(1H-tetrazol-5- yl)phenyl)-8-(4- methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 384.9 210

4-(2-(1-tetrahydro-2H- pyran-4-yl)-1H-pyrazolo-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzoic acid 405.1 211

4-(8-(3-fluorophenyl)-6- methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 363.1 212

4-(6-chloro-8-(3- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 383.0 213

(R)-4-(2-(1- ((tetrahydrofuran-2- yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1m,5- a]pyridin-8-yl)benzonitrile 386.3 214

(S)-4-(2-(1- ((tetrahydrofuran-2- yl)methyl)-1H-pyrazolo-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 386.3 215

4-(8-(3,4-difluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 367.1 216

4-(8-(3-fluorophenyl)-7- methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 363.1 217

4-(6-chloro-8-(3- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N,N- dimethylbenzamide 410.1 218

4-(8-(2-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoicacid 349.3 219

4-(8-o-tolyl- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid344.9 220

4-(8-(3-fluorophenyl)-6- methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N,N- dimethylbenzamide 390.1 221

4-(8-(3-fluorophenyl)-6- methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N- methylbenzamide 376.1 222

4-(6-chloro-8-(3- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N- methylbenzamide 396.1 223

4-(8-(3-fluorophenyl)-7- methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N,N- dimethylbenzamide 390.1 224

4-(8-(3-chloro-4- fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 383.1 225

8-(2-(4- carboxyphenylamino)- [1,2,4]triazolo[1,5-a]pyridin-8-yl)-2-fluorobenzoic acid 393.1 226

(R)-4-(2-(1-((1- methylpyrrolidin-2- yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 399.1 227

(S)-4-(2-(1-((1- methylpyrrolidin-2- yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzonitrile 399.1 228

4-(2-(1H-pyrazol-4- ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzonitrile 302.1 229

4-(8-(3-fluorophenyl)-7- methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 379.1 230

methyl 4-(8-(1-isobutyl-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 391.1 231

4-(8-(3- (hydroxymethyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 361.0 232

4-(8-(3- (dimethylcarbamoyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 402.0 233

methyl 4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate 407.1 234

4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 393.0 235

4-(8-(3-fluorophenyl)-7- methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N,N- dimethylbenzamide 406.1 236

(4-(8-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)(morpholino) methanone 462.1 237

methyl 4-(8-(1-(pyridin-2- ylmethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 426.1 238

methyl 4-(8-(1-(pyridin-3- ylmethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 426.1 239

4-(8-(1-(pyridin-2-ylmethyl)- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 412.1 240

4-(8-(1-(pyridin-3-ylmethyl)- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 412.1 241

4-(8-(1-(2-morpholinoethyl)- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 434.1 242

3-chloro-5-(8-(1- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)picolinic acid 396.9 243

4-(8-(2-chlorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoicacid 364.7 244

4-(8-(3-(1- hydroxyethyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 375.0 245

4-(8-(3-acetylphenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoicacid 373.0 246

4-(8-(3- (aminomethyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 359.9 247

4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzonitrile 329.9 248

4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzenesulfonamide 384.0 249

N-(4-(aminomethyl)phenyl)- 8-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 334.2 250

4-(8-fluoro-2-(1-tetrahydro- 2H-pyran-4-yl)-1H-pyrazol- 4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin- 8-yl)benzonitrile 404.1 251

6-fluoro-N-(1-((1- methylpyrrolidin-3- yl)methyl)-1H-pyrazol-4-yl)-5-(4- (methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-amine470.1 252

methyl 4-(2-(1-((1- methylpyrrolidin-3- yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzoate 432.1 253

4-(8-(3-(1- aminoethyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 374.1 254

4-(8-(3-carbamoylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 373.8 255

(4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)phenyl)methanol 354.8 256

4-(2-(1-((1-methylpyrrolidin- 3-yl)methyl)-1H-pyrazol-4-ylamino)-[1,2,4]triazolo[1,5- a]pyridin-8-yl)benzoic acid 418.1 257

4-(8-(1-((tetrahydro-2H- pyran-4-yl)methyl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 419.1 258

4-(8-(1-(2,2,2- trifluoroethyl)-1H-pyrazol-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 403.0 259

4-(8-(2-isopropylpyridin-4- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 374.1 260

N-(4-(6-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)acetamide 383.8 261

N-(4-(6-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenyl)methanesul- fonamide 398.0 262

1-(4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)phenyl)ethanol 348.8 263

5-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-3,3-dimethylindolin-2-one 388.3 264

methyl 4-(8-(1- ((tetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 419.1 265

methyl 4-(8-(1-((3- methyloxetan-3-yl)methyl)- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 419.1 266

methyl 4-(8-(1-(oxetan-3- yl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 391.1 267

4-(8-(1-((tetrahydrofuran-3- yl)methyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 405.1 268

4-(8-(1-((3-methyloxetan-3- yl)methyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 405.1 269

4-(8-(1-(oxetan-3-yl)-1H- pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 377.1 270

N-(4-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)phenylsulfonyl) acetamide 447.7 M + Na 271

N-(4-(4H-1,2,4-triazol-3- yl)phenyl)-8-(3- fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 372.2 272

methyl 6-(8-(3- isopropylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)nicotinate 386.1 273

methyl 5-(8-(3- isopropylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)picolinate 366.1 274

methyl 4-(8-(1- (cyclopropylmethyl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 369.1 275

methyl 4-(8-(1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2- ylamino)benzoate 419.1 276

4-(8-(1-(tetrahydro-2H- pyran-4-yl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-ylamino)benzoic acid 405.1 277

6-(8-(3-isopropylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)picolinic acid 374.1 278

4-(8-(3- (methylcarbamoyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 386.1 279

N-(4-(1-aminoethyl)phenyl)- 8-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 331   M − NH₂ 280

methyl 4-(8-(6- methoxypyridin-3-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate 376.1 281

4-(8-(6-methoxypyridin-3- yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 362.1 282

methyl 4-(8-(3,5- dimethoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate 405.1 283

4-(8-(3,5- dimethoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 391.1 284

6-(8-(3-isopropylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)nicotinic acid 374.2 285

methyl 4-(8-(3-tert-butyl-5- methylphenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 415.1 286

methyl 4-(8-(3-chloro-5- methylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate 393.0 287

4-(8-(3-tert-butyl-5- methylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 401.2 288

4-(8-(3-chloro-5- methylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 379.0 289

methyl 4-(8-(1-isopropyl- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 377.1 290

methyl 4-(8-(1-cyclohexyl- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzamide 417.1 291

4-(8-(1-isopropyl-1H- pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 363.1 292

4-(8-(1-cyclohexyl-1H- pyrazol-4-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 403.1 293

N-(1H-benzo[d]imidazol-5- yl)-8-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin- 2-amine 344.6 294

4-(8-(3-chloro-5- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 395.0 295

methyl 4-(8-(5-chloro-6- methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 410.1 296

methyl 4-(8-(5-fluoro-6- methoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 394.1 297

4-(8-(3-chloro-5- methoxypyridin-3-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 395.2 298

methyl 4-(8-(pyridin-3-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate 346.4 299

4-(8-(4-methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-3-methylbenzoic acid 375.1 300

4-(8-(5-fluoro-6- methoxypyridin-3-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 380.3 301

4-(8-(pyridin-3-yl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoicacid 332.3 302

5-(8-(3-fluorophenyl)- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)-3,3-dimethylisoindolin-1-one 388.2 303

methyl 4-(8-(2-chloro-4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate 409.1 304

methyl 4-(8-(4-methoxy-2- methylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoate 389.1 305

4-(8-(2-chloro-4- methoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 395.1 306

4-(8-(4-methoxy-2- methylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzoic acid 375.1 307

4-(8-phenyl- [1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 331.1308

methyl 4-(8-(1-((2,2- difluorocyclopropyl)methyl)- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoate 425.1 309

4-(8-(1-((2,2- difluorocyclopropyl)methyl)- 1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 411.1 310

4-(8-(1-(2- (dimethylamino)ethyl)-1H- pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin- 2-ylamino)benzoic acid 392.1 311

methyl 4-(8-(1-(2- (dimethylamino)ethyl)-1H- pyrazol-4-yl)-[1,2,4]triazol[1,5-a]pyridin- 2-ylamino)benzoate 406.2 312

8-(3,4-difluorophenyl)-N- (oxetan-3-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine 303.0

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as defined by the claims.

What is claimed is:
 1. A compound of Formula I

enantiomers, diasteriomers, tautomers or pharmaceutically acceptablesalts thereof, wherein: R¹ is H, C(O)OR

, phenyl, C₁-C₉ heterocyclyl or C₁-C₉ heteroaryl, wherein said phenyl,and heteroaryl are optionally substituted by 1 to 5 R⁶; R² is a phenyl,C₁-C₉ heteroaryl or C₁-C₉ heterocyclyl, wherein the phenyl, heteroaryland heterocyclyl are optionally substituted by 1 to 5 R⁷; R³, R⁴ and R⁵are independently H, CH₃, CH₂CH₃, OCH₃CF₃, F or Cl; R⁶ is independentlyH, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆ alkyl)OR^(a),(C₀-C₆ alkyl)NR^(a)R^(b), halo, CN, CF₃, S(O)O₁₋₂NR^(a)R^(b),C(O)OR^(a), NR^(a)C(O)OR^(b), NR^(a)S(O)₁₋₂NR^(b), (C₀-C₆alkyl)C₁-C_(5 heteroaryl, (C) ₀-C₆ alkyl)C₁-C₅ heterocyclyl, (C₀-C₆alkyl)C₃-C₆ cycloalkyl, (C₀-C₆ alkyl)C₆-C₉ aryl, (C₀-C₆ alkyl)C(O)OR

, C(O)O(C₀-C₅ alkyl)NR_(a)R^(b), C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl), C(O)NR^(a)(C₀-C₅ alkyl)(C₃-C₆cycloalkyl), C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heteroaryl), C(O)NR

(C₁-C₅ alkyl)NR^(a)R^(b) or C(O)NR^(a)(C₀-C₅ alkyl)(C₆ aryl), whereinsaid alkyl, alkenyl and alkynyl are optionally substituted by 1 to 5substituents independently selected from OR

, NR^(c)R^(d), oxo, halo, CF₃, and said aryl, heterocyclyl, heteroaryland cycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl, (C₀-C₆ alkyl)C₁-C₅heterocyclyl and C(O)(C₁-C₄ ; R⁷ is independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), (C₀-C₆ alkyl) (C₆-C₉ aryl), halo,C(O)NR^(a)R^(b), NR

C(O)R^(b), SO₂(C₁-C₆ alkyl), SO₂NR^(a)R^(b), CN, CF₃, CH₂CF³, nitro,S(O)(C₁-C₆ alkyl), S(O)NR^(a)R^(b), NR

S(O)₁₋₂R^(b), C(O)R

, C(O)OR

, (C₀-C₆ alkyl)C₁-C₅ heteroaryl, (C₀-C₆ alkyl)C₁-C₅ heterocyclyl or(C₀-C₆ alkyl)C₃-C₆ cycloalkyl, wherein said alkyl, alkenyl and alkynylare optionally substituted by 1 to 5 substituents independently selectedfrom oxo, NR^(a)R^(b), OR

, and halo, and said aryl, heteroaryl, heterocyclyl and cycloalkyl areoptionally substituted by 1 to 5 substituents independently selectedfrom OR

, halo, CF₃, NR^(c)R^(d) and C₁-C₄ alkyl; R^(a) R^(b) are independentlyH, OR

, C(O)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C₆ aryl or C₃ -C₆ cycloalkyl, whereinsaid alkyl, aryl and cycloalkyl are optionally substituted by 1 to 5substituents independently selected from C₁-C₄ alkyl, (C₀-C₃alkyl)OR^(c), oxo, halo, NR^(c)R^(d) and C₄-C₅ heterocyclyl; or R^(a)and R^(b) together with the atom to which they are attached form a C₁-C₅heterocyclyl; and R^(c) and R^(d) are independently H, C₁-C₃ alkyl,C₃-C₆ cycloalkyl or phenyl, wherein said alkyl, cycloalkyl and phenylare optionally substituted by 1 to 5 substituents independently selectedfrom halo, CH₃, OH or NH₂, C(O)O(C₃-C₆ alkyl) and C(O)NH(C₁-C₆ alkyl).2. The compound of claim 1, selected from Formula I:

enantiomers, diasteriomers, tautomers or pharmaceutically acceptablesalts thereof, wherein: R¹ is H, C(O)OR

, phenyl or C₁-C₉ heteroaryl, wherein said phenyl and heteroaryl areoptionally substituted by 1 to 5 R⁶; R² is phenyl, C₁-C₉ heteroaryl orC₁-C₉ heterocyclyl, wherein the phenyl, heteroaryl and heterocyclyl areoptionally substituted by 1 to 5 R⁷; R³, R⁴ and R⁵ are independently H,CH₃, CH₂CH₃, CF₃, F or Cl; R⁶ is independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), halo, CN, C₁-C₅ heteroaryl, C₁-C₅heterocyclyl, C₃-C₆ cyclalkyl, C₆-C₉ aryl, C(O)OR

, C(O)(C₀-C₅ alkyl)NR^(a)R^(b), C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl), C(O)NR

(C₀-C₅ alkyl)(C₃-C₆ cycloalkyl), C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅heteroaryl, C(O)NR^(a)(C₁-C₅ alkyl)NR^(a)R^(b), or C(O)NR

(C₁-C₅ alkyl)(C₆ aryl), wherein said alkyl, alkenyl and alkynyl areoptionally substituted by 1 to 5 substituents independently selectedfrom OR

, NR^(c)R^(d), oxo, and halo, and said aryl, heterocyclyl, heteroaryland cycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl); R⁷ isindependently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), (C₀-C₆ alkyl)(C₆-C₉aryl), halo,C(O)NR^(a)R^(b), NR^(a)C(O)R^(b), SO₂(C₁-C₆ alkyl), SO₂NR^(a)R^(b), CN,nitro, wherein said alkyl, alkenyl and alkynyl are optionallysubstituted by 1 to 5 substituents independently selected from oxo andhalo, and said and said aryl is optionally substituted by 1 to 5substituents independently selected from OR

, halo, CF₃, NR^(c)R^(d) and C₁-C₄ alkyl; R^(a) and R^(b) areindependently H, OR^(c), C(O)O(C₁-C_(6 alkyl) C) ₁-C₆ alkyl, C₆ aryl orC₃-C₆ cycloalkyl, wherein said alkyl, aryl and cycloalkyl are optionallysubstituted by 1 to 5 substituents independently selected from C₁-C₄alkyl, (C₀-C₃ alkyl)OR

, oxo, halo, NR^(c)R^(d) and C₄-C₅ heterocyclyl; or R^(a) and R^(b)together with the atom to which they are attached form a C₁-C₅heterocyclyl; and R^(c) R^(d) are independently H, C₁-C₃ alkyl, C₃-C₆cycloalkyl or phenyl, wherein said alkyl, cycloalkyl and phenyl areoptionally substituted by 1 to 5 substituents independently selectedfrom halo, CH₃, OH, NH₂, C(O)O(₁-C₆ alkyl) and C(O)NH(C₁-C₆ alkyl). 3.The compound of claim 1, wherein R¹ is phenyl or C₁-C₉ heteroaryl,wherein said phenyl and heteroaryl are optionally substituted by 1 to 5R

.
 4. The compound of claim 3, wherein R¹ is phenyl optionallysubstituted by 1 to 5 R

.
 5. The compound of claim 3, wherein R¹ is phenyl optionallysubstituted by 1 to 5 R

.
 6. The compound of claim 5, wherein C₁-C₉ heteroaryl is pyridinyl,imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, trazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinoxalinyl, quinoxalinyl, naphthyridinyl or furopyridinyl, each ofwhich is optionally substituted by 1 to 5 R

.
 7. The compound of claim 6, wherein said C₁-C₉ heteroaryl ispyrindinyl optionally substituted by 1 to 4 R⁶.
 8. The compound of claim3, wherein R⁶ is independently C₁-C₆ alkyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), halo, CN, C₁-C₅ heteroaryl, C₄-C₅heterocyclyl, C₃-C₆ cycloalkyl, C₆ aryl, C(O)OR

, C(O)(C₀-C₅ alkyl)NR^(a)R^(b), C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl), C(O)NR

(C₀-C₅ alkyl)(C₃-C₆ cycloalkyl), C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heteroaryl), C(O)NR

(C₁-C₅ alkyl)NR^(a)R^(b), C(O)NR^(a)C₁-C₅ alkyl)C₆ aryl), wherein saidalkyl is optionally substituted by 1 to 5 substituents independentlyselected from OR

, NR^(c)R^(d), oxo and halo, and said aryl, heterocyclyl, heteroaryl andcycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl).
 9. Thecompound of claim 8, wherein R⁶ is C₄-C₅ heterocyclyl optionallysubstituted by 1 to 5 substituents independently selected from OH, oxo,halo, CF₃, NR^(c)R^(d), C₁-C

alkyl and C(O)(C₁-C₄ alkyl).
 10. The compound of claim 9, whereinheterocyclyl is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,1,1-dioxotetrahydrothiophenyl, piperdinyl, piperizinyl,tetrahydropyranyl, thianyl, morpholinyl, pyridizinyl orhexahydroprimidinyl.
 11. The compound of claim 9, wherein saidheterocyclyl is piperdinyl, piperizinyl or morpholinyl.
 12. The compoundof claim 8, wherein R⁶ is (C₀-C₆ alkyl)OR

or (C₀-C₆ alkyl)NR^(a)R^(b).
 13. The compound of claim 12, wherein R⁶ is(C₀-C₆ alkyl)OR

or (C₀-C₃ alkyl)NR^(a)R^(b).
 14. The compound of claim 8, wherein R⁶ ishalo.
 15. The compound of claim 14, wherein R⁶, is F or Cl.
 16. Thecompound of claim 8, wherein R⁶ is C(O)NR^(a)(C₀-C₅ alkyl)(C₁-C₅heterocyclyl), C(O)NR

(C₀-C₅ alkyl)(C₃-C₆ cycloalkyl), C(O)NR

(C₀-C₅ alkyl)(C₁-C₅ heteroaryl), C(O)NR

(C₁-C₅ alkyl)NR^(a)R^(b), C(O)NR

(C₁-C₅ alkyl)(C₆ aryl), wherein said alkyl is optionally substituted by1 to 5 substituents independently selected from OR

, NR^(c)R^(d), oxo and halo, and said aryl, heterocyclyl, heteroaryl andcycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl). 17.The compound of claim 8, wherein R⁶ is C(O)OR

, C(O)(C₀-C₅ alkyl)NR^(a)R^(b) or C(O)(C₀-C₅ alkyl)(C₁-C₅ heterocyclyl),wherein said alkyl is optionally substituted by 1 to 5 substituentsindependently selected from OR

, NR^(c)R^(d), oxo, and halo, and said aryl, heterocyclyl, heteroaryland cycloalkyl are optionally substituted by 1 to 5 substituentsindependently selected from OR

, oxo, halo, CF₃, NR^(c)R^(d), C₁-C₄ alkyl and C(O)(C₁-C₄ alkyl). 18.The compound of claim 1, wherein R¹ is H.
 19. The compound of claim 1,wherein R¹ is C(O)OR

, wherein R

is independently H, OR

, C(O)O(C₁-C₆ alkyl), C₁-C₆ alkyl, C₆ aryl or C₃-C₆ cycloalkyl, whereinsaid alkyl, aryl, and cycloalkyl are optionally substituted by 1 to 5substituents independently selected from C₁-C₄ alkyl, (C₀-C₃ alkyl)OR

, oxo, halo, NR^(c)R^(d) and C₄-C₅ heterocyclyl.
 20. The compound ofclaim 1, wherein R³, R⁴ and R⁵ are independently H, CH₃, CF₃, or F. 21.The compound of claim 1, wherein R³, R⁴ and R⁵ are independently H or F.22. The compound of claim 1, wherein R³, R⁴ and R⁵ are H.
 23. Thecompound of claim 1, wherein R² is a phenyl, C₁-C₉ heteroaryl or C₁-C₉heterocyclyl, wherein the phenyl, heteroaryl and heterocyclyl areoptionally substituted by 1 to 5 R⁷;
 24. The compound of claim 23,wherein R² is a phenyl optionally substituted by 1 to 5 R⁷.
 25. Thecompound of claim 24, wherein R⁷ is independently C₁-C₆ alkyl, (C₀-C₆alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), (C₀-C₆ alkyl)(C₆-C₉aryl), halo,C(O)NR^(a)R^(b), NR

C(O)R^(b), SO₂(C₁-C₆ alkyl), SO₂NR^(a)R^(b), CN, nitro, wherein saidalkyl is optionally substituted by 1 to 5 substituents independentlyselected from oxo and halo, and said aryl is optionally substituted by 1to 5 substituents independently selected from OR

, halo, CF₃, NR^(c)R^(d) and C₁-C₄ alkyl.
 26. The compound of claim 25,wherein R

is independently C₁-C₄ alkyl, (C₀-C₆ alkyl)OR

, (C₀-C₆ alkyl)NR^(a)R^(b), halo, NR

C(O)R

, SO₂(C₁-C₆ alkyl), SO₂NR^(a)R^(b), CN or nitro.
 27. The compound ofclaim 26, wherein R

is independently NH₂, OCH₃, CH₃, CH₂CH₃, CH(CH₃)₂), NO₂, OCF₃,S(O)₂N(CH₃)₂, S(O)NH(CH(CH₃)₂), S(O)₂NH(C(CH₃)₃), CN, CF₃, F, Cl,NHC(O)CH₃ or S(O)₂CH₃.
 28. The compound of claim 23, wherein R² is C₁-C₉heteroaryl optionally substituted by 1 to 5 R

.
 29. The compound of claim 28, wherein C₁-C₉ heteroaryl is pyridinyl,imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, trazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinoxalinyl, quinoxalinyl, naphthyridinyl or furopyridinyl, each ofwhich is optionally substituted by 1 to 5 R⁷.
 30. The compound of claim29, wherein said C₁-C₉ heteroaryl is pyrindinyl optionally substitutedby 1 to 5 R

.
 31. The compound of claim 30, wherein R

is independently CH₃ CH₂(phenyl), CH₂CH(CH₃)₂, or CF₃.
 32. The compoundof claim 23, wherein said R² is C₃-C₅ heterocyclyl optionallysubstituted by 1 to 5

.
 33. The compound of claim 32, wherein R² is piperidinyl, morpholinylor piperizinyl optionally substituted by 1 to 5 R

.
 34. The compound of claim 33, wherein R⁷ is independently CH₃, CH₂CH₃,OH or OCH₃.
 35. The compound of claim 1, wherein R¹ is phenyl,optionally substituted by 1 to 5 R⁶; and R² is phenyl, optionallysubstituted by 1 to 5 R⁷.
 36. The compound of claim 1, wherein R¹ isphenyl, optionally substituted by 1 to 5 R⁶; and R² is heterocyclyl,optionally substituted by 1 to 5 R

.
 37. The compound of claim 36, wherein said heterocyclyl ispiperidinyl, morpholinyl or piperizinyl.
 38. The compound of claim 1,wherein R¹ is pyridyl, optionally substituted by 1 to 5 R⁶; and R² isphenyl, optionally substituted by 1 to 5 R⁷.
 39. The compound of claim1, wherein R¹ is pyridyl, optionally substituted by 1 to 4 R⁶; and R² isheterocyclyl, optionally substituted by 1 to 5 R⁷.
 40. The compound ofclaim 39, wherein said heterocyclyl is piperidinyl, morpholinyl orpiperizinyl.
 41. The compound of claim 1, wherein R¹ is pyridyl,optionally substituted by 1 to 5 R⁶; and R² is phenyl, optionallysubstituted by 1 to 5 R⁷.
 42. The compound of claim 1, wherein R¹ ispyridyl, optionally substituted by 1 to 4 R⁶; and R² is pyridyl,optionally substituted by 1 to 5 R⁷.
 43. A compound selected from:


44. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier, adjuvant or vehicle.
 45. Thecomposition of claim 44, further comprising an additional therapeuticagent selected from an anti-proliferative agent, and anti-inflammatoryagent, an immunomodulatory agent, a neurotropic factor, an agent fortreating cardiovascular disease, an agent for treating liver disease,and anti-viral agent, an agent for treating blood disorders, an agentfor treating diabetes, or an agent for treating immunodeficiencydisorders.
 46. A pharmaceutical composition comprising a compound ofclaim 1 in an amount to detectably inhibit JAK2 kinase activity and apharmaceutically acceptable carrier, adjuvant or vehicle.
 47. A methodof treating or lessening the severity of a disease or conditionresponsive to the inhibition of JAK2 kinase activity in a patient,comprising administering to a patient a therapeutically effective amountof a compound of claim
 1. 48. The method of claim 47, wherein saiddisease or condition is cancer, stroke, diabetes, hepatomegaly,cardiovascular disease, multiple sclerosis, Alzheimer's disease, cysticfibrosis, viral disease, autoimmune diseases, atherosclerosis,restenosis, psoriasis, allergic disorders, inflammation, inflammatorydiseases, neurological disorders, a neurodegenerative disease, ahormone-related disease, conditions associated with organtransplantation, immunodeficiency disorders, destructive bone disorders,proliferative disorders, infectious disease, conditions associated withcell death, thrombin-induced platelet aggregation, liver disease,pathologic immune conditions involving T cell activation, CNS disorderor a myeloproliferative disorder.
 49. The method of claim 48, whereinsaid disease or condition is cancer.
 50. The method of claim 48, whereinsaid disease is a Myeloproliferative disorder.
 51. The method of claim50, wherein said myeloproliferative disorder is polycythemia vera,essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia(CML).
 52. The method of claim 49, wherein the cancer is breast, ovary,cervix, prostate, testis, penile, genitourinary tract, seminoma,esophagus, larynx, gastric, stomach, gastrointestinal, skin,keratoacanthoma, follicular carcinoma, melanoma, lung, small cell lungcarcinoma, non-small cell lung carcinoma (NSCLC), lung adenocarcinoma,squamous carcinoma of the lung, colon, pancreas, thyroid, papillary,bladder, liver, biliary passage, kidney, bone, myeloid disorders,lymphoid disorders, hairy cells buccal cavity and pharynx (oral), lip,tongue, mouth, salivary gland, pharynx, small intestine, colon, rectum,anal, renal, prostate, vulval, thyroid, large intestine, endometrial,uterine, brain, central nervous system, cancer of the peritoneum,hepatocellular cancer, head cancer, neck cancer, Hodgkin's or leukemia.53. The method of claim 48, wherein cardiovascular disease isrestenosis, cardiomegaly, atherosclerosis, myocardial infarction orcongestive heart failure.
 54. The method of claim 48, whereinneurodegenerative disease is Alzheimer's disease, Parkinson's disease,amyotrohpic lateral sclerosis, Huntington's disease, and cerebralischemia, and neurodegenerative disease caused by traumatic injury,glutamate neurotoxicity or hypoxia.
 55. The method of claim 48, whereininflammatory disease is rheumatoid arthritis, psoriasis, contactdermatitis or delayed hypersensitivity reactions.
 56. The method ofclaim 47, further comprising administering a second chemotherapeuticagent.
 57. A kit for treating a disease or disorder responsive to theinhibition of a JAK kinase, comprising: (a) a first pharmaceuticalcomposition comprising a compound of claim 1; and (b) instructions foruse.
 58. The kit of claim 57, further comprising: (c) a secondpharmaceutical composition, comprising a chemotherapeutic agent.
 59. Thekit of claim 58, wherein said instructions comprise instructions for thesimultaneous, sequential or separate administration of said first andsecond pharmaceutical compositions to a patient in need thereof.
 60. Thekit of claim 58, wherein said first and second compositions arecontained in separate containers.
 61. The kit of claim 58, wherein saidfirst and second compositions are contained in the same containers. 62.A compound of claim 1, selected from a compound of Examples 1-312.